JPS60226862A - Antiviral pyrid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to antiviral agents, pharmaceutical compositions containing the agents, and methods for treating warm-blooded animals suffering from viral diseases.

B. philus infection is generally believed to be the cause of many diseases of various nature, such as rabies, hepatitis, herpes, and the common cold. The common cold is widespread throughout the world and is a major cause of illness and absenteeism. Drugs capable of treating such diseases would be of great benefit to humanity and certainly of great economic importance.

To date, no such drugs are available and there are no established chemotherapeutic agents for the disease.

The present invention discloses the useful antiviral properties of a number of pyridazine derivatives and their use in the treatment of viral diseases. Certain of the pyridazine amines of this invention are known in the art as intermediates for the synthesis of other useful compounds or as compounds with certain pharmacological properties. These compounds and compounds similar to structural i can be found in the following literature:

J. Med. Chem. 24.59-63 (1981)
A number of IH-imidazolyl-pyridasis have been described in European Patent No. 55.583, US Pat. No. 4.110.450, US Pat.
No. 385 and No. 2,985,657 describe a number of piperazinyl, pyrrolidinyl and piperidinyl substituted pyridazines as intermediates. Furthermore, in European Patent No. 9,655, 3-chloro-6-[4-(2-methoxyphenyl)-1-piperazinyl]pyridazine and l-chloro-4-(4-hydroxypiperidino)phthalazine are used as intermediates. described as a body. J, Med as compounds in which more substituted 1-piperazinyl-pyridazines have anti-adrenergic, antihistamine or analgesic activity.

Chem, 6.541-4 (1963), 8.104
-107 (1965) and 15.295-301 (1965)
972).

The compounds of the present invention differ from the cited compounds known in the art by specific substitutions in the pyridazine moiety and, in particular, by their useful antiviral properties.

According to the present invention, structurally, R1 is hydrogen, halo, IH-imidazol-1-yl, lower alkyloxy, aryloxy, aryl-lower alkyloxy, lower alkylthio, arylthio, hydroxy, mercapto, amino, lower alkyl a member selected from the group consisting of sulfinyl, lower alkylsulfonyl, cyanide, lower alkyloxycarbonyl, lower alkylcarbonyl and lower alkyl; R2 and R3 are each independently selected from the group consisting of hydrogen and lower alkyl; or R2 and Rs can be combined to form a divalent group of the formula -CH=CH-CH=CH-; may be substituted with lower alkyl or aryl; m and n are each independently an integer from 1 to 4;
and the sum of m and n is 3.4 or 5; R4 is hydrogen; lower alkyl; aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl; lower alkyloxycarbonyl; aryl lower alkyl;
Diaryl lower alkyl: phenyl substituted with arylcarbonyl; pyridinyl optionally substituted with cyano or lower alkyl; optionally substituted with up to two substituents independently selected from the group consisting of cyano and aryl. A member selected from the group consisting of both cyclohexyl and cyclohexenyl; (・5 is hydrogen; lower alkyl; aryl; hydroxy; lower alkyloxy; aryloxy; morpholine;
Lower alkyloxy substituted with pyrrolidine or piperidine; Amino: (lower alkyloxycarbonyl) amino; Arylamino; (aryl) (lower alkyl)
Amino; (aryl lower alkyl) amino; (aryl lower alkenyl) amino: (aryl lower alkenyl)
(lower alkyl)amino; arylcarbonyloxy; R6 is hydrogen; aryl; lower alkyl; (lower alkylcarbonylamino) lower alkyl; aryl lower alkyl; arylcarbonyl lower alkyl; aminocarbonyl: arylcarbonyl; arylaminocarbonyl;
(aryl lower alkyl) carbonyl; lower alkyloxycarbonyl; indolyl; pyridinyl; R″ and R1 each independently represent hydrogen, lower alkyl,
Aryl is a member selected from the group consisting of aryl, aryl lower alkyl and pyridinyl; said aryl is a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, nitro, amino, lower alkyloxy, hydroxy and lower alkyloxycarbonyl; chenyl; and naphthalenyl. Antivirally active pyridazine amines, which are phenyl optionally substituted with up to three substituents independently selected from the group, and pharmaceutically acceptable acid addition salts thereof. as well as/
or its possible stereochemically isomeric forms and/or its possible tautomeric forms.

The term "halo" as used in the above definitions generally includes fluoro, chloro, bromo and iodo; "lower alkyl" includes straight-chain and branched saturated Hydrocarbon groups such as methyl, ethyl, 1
-Methyl ethyl, 1゜1-dimethylethyl, propyl,
is meant to include methyl, pentyl, hexyl, etc.; "lower alkenyl" refers to alkenyl having from 2 to about 6 carbon atoms, e.g., 2-flobenyl, 2-butenyl, 3
-butenyl, 4-pentenyl, etc.

Compounds of formula (I) are generally prepared by converting amines of formula (If) into compounds of formula (If) according to N-alkylation methods known in the art.
It can be produced by N-alkylation with the reagent 1).

1) In formula (1), W is a suitable reactive leaving group, such as halo, i.e. fluoro, chloro, bromo or iodo, or a sulfonyloxy group, such as methylsulfonyloxy or 4-methylphenylsulfonyloxy, lower Represents an alkyloxy or lower alkylthio group.

The alkylation reaction is carried out using an inert organic solvent such as aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; lower alkanols such as methanol, ethanol, l-butanol, etc.; ketones such as 2-propanone, 4-methyl -2-pentanone, etc.; ethers, such as 1,4-dioxane% 111'-oxybisethane, tetrahydrofuran, etc.; dipolar aprotic solvents,
For example, N,N-dimethylformamide (DMF);
N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); nitrobenzene; l-methyl-2
-Pyrrolidinone; can advantageously be carried out in equal widths. In order to collect the acid liberated during the reaction process, a suitable base,
For example, alkali metal carbonates or hydrogen carbonates, hydrides) or organic bases, such as N,N-diethylethanamine or N-(l-methylethyl)-2-
Addition of propanamine can be used. In some cases, iodide salts, preferably alkali metal iodides, are suitable. The alkylation reaction can also be carried out by mixing and/or melting the reactants together, optionally in the presence of a base as described above. Slightly elevated temperatures can be used to speed up the reaction rate.

The compounds of formula (1) can also be converted into each other by suitable functional group rearrangement reactions. For example, A is the formula (b),
However, the compound of formula (1), which is a group in which R4 is hydrogen, and the compound is represented by formula (1-a), is represented by formula (It
) and 1t) can be alkylated or acylated with a reagent of formula (IV) according to the method described above in preparing formula (1), thus giving a compound of 2-b). can.

(I-a) R2flB (1-b)' In formula (rV), W has the meaning already defined,
And R4-a is the same as R4, except that it is not hydrogen.

A compound of formula (1), wherein R is lower alkyl, aryl lower alkyl, diaryl lower alkyl, cyclohexyl or cyclohexenyl, and R is represented by R4-b; is expressed as the formula (1-
C) represents a compound of formula-b-1 (1-a) with a suitable formula (R,)=c=o, the (
R)=c=o is a compound of the formula R4-bH, 4-b-1, where the -CH,- group is oxidized to a carbonyl group, prepared by reductive N-alkylation with a carbonyl compound of be able to.

-b-1 (R)=C=0+(1-a)-1 → 1R3 (1-C) The reductive N-alkylation reaction is carried out by an appropriate reaction according to the catalytic hydrogenation method known in the art. This can advantageously be carried out by catalytic hydrogenation of a stirred and heated mixture of the reactants in a naturally inert organic solvent. The reaction mixture can be stirred and/or heated to speed up the reaction rate. Suitable solvents are, for example, water; lower alkanols, such as methanol, ethanol, 2-propanol, etc.; monkey ethers, such as 1,4-dioxane;
halogenated hydrocarbons such as trichloromethane; N,N-dimenalformamide; dimethyl sulfoxide and the like; or mixtures of two or more such solvents. The term "catalytic hydrogenation processes known in the art" means that the reaction is carried out under an atmosphere of hydrogen and in the presence of a suitable catalyst, such as palladium on charcoal, platinum on charcoal, etc. . In order to prevent further undesired hydrogenation of certain functional groups in the reactants and reaction products, it may be advantageous to add a suitable catalyst poison, such as naofene, to the reaction mixture.

A compound of formula (1) in which A is a group of formula (b), sushi, l (4 is hydrogen), is prepared by treating the compound in the presence of a suitable solvent, such as a hydrocarbon such as benzene, methylbenzene, etc. , by reacting with a suitable cyclohexanone derivative,
It can be converted to the corresponding compound where R4 is optionally substituted 2-cyclohexenyl. In some cases it may be advantageous to supplement the reaction mixture with a suitable acid, such as 4-methylsulfonic acid.

Or, conversely, a compound of formula (I) in which A is a group of formula (b), in which R4 is lower alkyloxycarbonyl or lower alkylcarbonyl, can be prepared by preparing a compound of formula (I) according to methods known in the art, e.g. can be deacylated by reacting with a suitable acid or basic solution.

Similarly, compounds of formula (1) in which A is a group of formula (C), where RB is (lower alkyloxycarbonyl)amino, can be converted into the corresponding amino-compounds.

The compound of formula (1) in which A is a group of formula (C), provided that Rs is hydroxy, is removed by a removal reaction, where A is a group of formula (d
) can be converted into the corresponding compound of formula (1) which is a group of This reaction can be carried out by reacting the former with a suitable acidic solution, preferably at elevated temperature. Suitable acidic solutions include one or more acids, such as simulants, hydrochloric acid, vinegar.
Ik the water and/or an organic solvent, e.g. methanol,
Contained as a mixture with ethanol etc.

Alternatively, the starting hydroxy-containing compound is preferably dissolved in a suitable solvent such as pyridine, N,N-dimethylformamide (
It can be reacted with a suitable dehydroxylating agent such as phosphoryl chloride, thionyl chloride, phosphorus trichloride in the presence of DMF) or the like.

Compounds of formula (1) containing a cyclohexenyl group can be prepared by reducing the compound to a metal hydride, hydrogen chloride, etc. in an organic solvent, e.g. an alcohol such as methanol, optionally in the presence of a base, e.g. sodium methylate, etc. It can be converted to the corresponding cyclohexyl compound by reaction with sodium boronate.

Compounds of formula (1) in which R1 is halo can be prepared by reacting the halo-containing compound with a suitable aromatic or aliphatic alcohol or mercaptan, such that l(+ is lower alkyloxy, aryloxy, aryl lower alkyloxy, lower alkylthio). or can be converted to the corresponding compound that is arylthio.

This reaction can be carried out in a suitable solvent such as chthon, eg 2propanone, DMF', DMA, etc. In order to speed up the reaction rate, suitable bases can be added, for example alkali metal hydrides, such as hydrided 1-IJ cum, alkali metal carbonates, such as sodium carbonate. Alternatively, the starting halo compound is dissolved in a suitable alkali metal alcoholate, aryl oxide or (aryl substituted) in a suitable solvent, preferably the corresponding alcohol.
can be reacted with alcoholates, thus producing the desired compounds l(, l is lower alkyloxy, aryloxy and aryl lower alkyloxy).

Compounds of formula (I) in which R1 is arylmethyloxy can be prepared according to methods known in the art for the removal of arylmethyl groups, for example by treating the starting compound in an acidic solution or with hydrogen in the presence of a suitable catalyst in a suitable solvent. can be converted to the corresponding hydroxy compound by reacting with

Compounds of formula (1) in which R1 is halo can be prepared according to hydrogenolysis methods known in the art, i.e. the presence of a suitable catalyst, such as palladium on charcoal, of the starting compound in a suitable solvent. Below, it can be converted to the corresponding compound in which R' is hydrogen by heating under a hydrogen atmosphere.

Additionally, compounds of formula (I) in which I is halo can be prepared by reacting the compound with thiourea in the presence of hydrogen disulfide or a reagent capable of generating hydrogen disulfide, such as a base, to form the corresponding mercapto-containing compound. can be transformed.

Formula (1) where tjl is lower alkyloxycarbonyl
The compound is prepared by reacting the starting compound with a suitable ester in a suitable alcohol in the presence of an alkali metal.
It can be converted to the corresponding lower alkylcarbonyl compound.

The compounds of formula (1) have basic properties and are therefore suitable for use with suitable acids, such as inorganic acids, such as hydrohalic acids, such as hydrochloric acid, hydrobromic acid, etc., and di- or Organic acids such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, propanedioic acid, butanedioic acid, (Z)-2-butanedioic acid, @-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, engineered sulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, It can be converted to its therapeutically active non-toxic acid addition salt form by treatment with cyclohexane sulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc. Conversely, the salt form can be converted to the free base form by treatment with alkali.

Many of the intermediates and starting materials in the above preparations are known compounds, such as those described in U.S. Pat.
No. 97.472; No. 2,979,507, No. 2.
No. 997.474 and No. 3,002,976.

Formula (II) where A is a group of formula (b), provided that R4 is other than hydrogen, and R4 is represented by B4-a
an intermediate represented by formula (II-a),
can be prepared by alkylating an amine of formula M with a reagent of formula (IV), thus forming an intermediate of formula (Vl), followed by removal of the group P. In formulas (V) and (Vl), P is a suitable protecting group, such as lower alkyloxycarbonyl, arylmethoxycarbonyl, arylmethyl, arylsulfonyl, and the like. Removal of P in formula CVI) can generally be carried out according to methods known in the art, for example by hydrolysis in an alkaline or acidic medium.

Intermediates of Yota formula (Vl) are N
-According to the alkylation method, the amine of the formula (Vl) is converted to the amine of the formula (Vl).
It can also be produced by N-alkylation with a reagent.

(■) The reaction between formulas (IV) and (V) and formulas (■) and (■) is
Starting from formulas (n) and (1), one can follow the same methods described above for the preparation of formula (I).

A is a group of formula (C), provided that R6 is hydrogen and R5 is a group of formula -NR9)1.10, and the -NRIIRIO
is arylami/, (aryl)(lower alkyl)amino, (aryllower alkyl)amine, (aryllower alkenyl)(lower alkyl)amino, (aryllower alkenyl)amino, , wherein said intermediate is represented by formula (If-b), reductively N-alkylates a ketone of formula (rX) with an amine of formula (X), thus producing an intermediate of formula (XI). , and then removing the protecting group P. In formulas (IX) and (XI), P has the meaning already stated.

The reductive amination described above may advantageously be carried out by catalytic hydrogenation of the mixture of reactants in a suitable reaction-inert medium according to methods known in the art.

Intermediates of formula (It) in which A is a divalent group of formula (C), where R5 is hydrogen and R6 is aryl, lower alkyl or substituted lower alkyl, are intermediates of formula (It)
(2) can be produced by reacting with a suitable Grignard reagent in a suitable solvent. The hydroxy-containing intermediate thus obtained is either deprotected or further reacted with a suitable acid solution to remove the water molecule and then deprotected, thus forming a compound of formula (d) in which A is a group of formula (d). Intermediates of It) can be prepared.

The compound of formula CI) exhibits antiviral activity, combining desirable antiviral activity at low dosages, and its favorable therapeutic index resulting from an acceptably low degree of cytotoxicity (
It is particularly attractive for therapeutic index).

The useful antiviral properties of compounds of formula (I) are demonstrated in the following test method.

Rifvirus-susceptible Hela cells were treated with Minimal Essential Medium (Minimal Essential Me) without essential amino acids (Minimal Essential Me) supplemented with 5% inactivated calf fat serum.
dium) (MBM). Sow cells at 5%C
Culture was carried out overnight at 37°C under O3 atmosphere. 24 hours later,
Cells were treated with a solution of the test compound or a solution of the test compound in a solvent containing 1 part DM80 and 7 parts MEM supplemented with inactivated 10% calf serum. Both vehicle and drug treated cells were cultured for 3 hours at 37°C and then a standardized inoculum of human rhinovirus was added. Rhinovirus was grown in Hela cells for an additional incubation period at 33°C. Scoring of results was delayed until complete (100%) cytopathological effect was achieved in virus controls (vehicle and virus treated cells). Antiviral activity was determined by at least 7 of the cytopathological effects observed in the viral control.
It was scored as the lowest concentration of test drug in μg/-1 that inhibited 5%.

In addition, some of the compounds of the invention exhibit analgesic and antitussive properties, such as those of Arzneim.

Forsch, 25.1505-1509 (1975
) and Arzneim, Forschll5.107-
117 (1965).
This can be demonstrated by the AwalReflex test and the Writing test.

In view of their useful pharmacological properties, the compounds of formula (1) and their acid addition salts are extremely useful in the treatment of viral diseases.

To facilitate administration, the compounds can be formulated into a variety of pharmaceutical forms. To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound, in base or acid addition salt form, is incorporated as the active ingredient in intimate admixture with a pharmaceutically acceptable carrier; The carrier can take a wide variety of forms depending on the form of preparation desired for administration.

The pharmaceutical composition is preferably administered orally, rectally, transdermally,
Alternatively, a unitary dosage form suitable for parenteral injection is desirable. For example, in preparing compositions in oral dosage forms, common pharmaceutical vehicles are used, such as water, glycols, oils, alcohols, etc. in the case of oral liquid preparations, such as suspensions, syrups, elixirs and solutions. Alternatively, in the case of powders, emulsions, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. can be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually consists at least mostly of phaseless water, although other ingredients can be included, eg, to aid solubility. For example, injectable solutions can be prepared with a carrier consisting of a saline solution, a glucose solution, or a mixture of saline and glucose solution.

Injectable suspensions can also be prepared using suitable liquid carriers, suspending agents and the like.

In compositions suitable for transdermal administration, the optional carrier may comprise penetration enhancers and/or suitable wetting agents in small proportions in combination with suitable additives, which additives have no appreciable deleterious effect on the skin. It is something that cannot be brought about. The additives may facilitate administration to the skin and/or serve to produce the desired composition. These compositions can be administered in a variety of ways, e.g. transdermal mucosal, spot-on.
, can be administered as an ointment.

The acid addition salts of formula (1) are clearly more suitable in the preparation of aqueous compositions due to their increased solubility in water than the corresponding base forms.

It is especially advantageous to formulate the above pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable for unitary dosage, each unit producing the desired therapeutic effect in combination with the required pharmaceutical carrier. Contains a predetermined amount of active ingredient calculated for. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, emulsions, powder sachets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, etc. This is double the divided amount.

Further in accordance with the present invention, an antivirally effective amount of a compound of formula (1), a pharmaceutically acceptable acid addition salt thereof, a possible stereoisomeric or tautomeric form thereof, is administered systemically to a warm-blooded animal. A method of treating a viral disease in a warm-blooded animal suffering from the viral disease is provided, the method comprising administering the virus to a warm-blooded animal. The dosage administered to the patient per day is o, oiq ~ 1F
! , preferably in the range of 1q to 5QQMv.

A preferred method of treatment of viral diseases in warm-blooded animals infected with viral diseases is the formula % where R1% R2 and Bs have the meanings previously defined and AI is the formula (a), (C) or (d), with the proviso that i) R'', 几2 and R3 are hydrogen, and 81 is a group of formula (b), R4 is 3 .3-diphenylglopyr; 11) R' is hydrogen, and R1 and Rs combine to form a CH=CH-CH=CH group; 1ii) R' is halo and R2 is lower alkyl and R8 is hydrogen, other than -1H-azepinyl; IV) R' is chloro and A
When I is a divalent group of (Niwa), R4 is (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α
- menalufenethyl, = is other than C2-methylphenyl)methyl, a pharmaceutically acceptable acid addition salt thereof and/or
or of its possible stereoisomeric and/or tautomeric forms, systemically administering to a warm-blooded animal an antivirally effective amount.

Preferred compositions within the scope of the invention include an inert carrier and a compound of formula (1'), a pharmaceutically acceptable acid addition salt thereof and/or its possible stereochemically isomeric forms and/or its tautomeric forms. It consists of an antivirally effective amount of.

Furthermore, the present invention is characterized by some of the compounds of formula (1) and/or
or its pharmaceutically acceptable acid addition salts and/or its possible stereochemical isomers and/or its possible tautomeric forms are novel, and the compound has the formula: R11Bt and Ba has the meaning already stated;
and A has the formula (a), (C), (d) or 2-C-CmH2m-N-CnH2n-(b-1)
a valent group, with m and n having the meanings given above, and a group C1nH2ms
One of the hydrogen atoms in Cm-In2(m-1) or CnH2n may be substituted with lower alkyl or aryl; and R4-C is aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl, lower alkyloxy carbonyl; aryl lower alkyl; diaryl lower alkyl; phenyl substituted with arylcarbonyl; pyridinyl optionally substituted with cyano or lower alkyl; two substituents independently selected from the group consisting of cyano and aryl i) A'' is a group of formula (C) and Be is hydrogen, R3 is other than hydrogen, hydroxy or lower alkyl; 1t) When R', R'' and R3 are hydrogen and 82 is a group of formula (b-1), R4-
0 is other than 3,3-diphenylglopyr; il+)R'' and R3 are hydrogen and A2 is of the formula (
a), R1 is other than halo; 1v) when R' is chloro, R2 and Rs are hydrogen, and A2 is a group of formula (b-1), R1 is other than halo; is 2-
other than methoxyphenyl; v) When R' is chloro and A2 is a divalent group of formula (b-z), R4-0 is (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl , other than α-menalufenethyl or (2-methylphenyl)methyl.

A particularly clever method for the treatment of viral diseases in warm-blooded animals suffering from viral diseases is the use of compounds of formula (I"), their pharmaceutically acceptable acid addition salts and/or their possible stereochemical isomers. This is a method that depends on your body type.

Particularly preferred compositions within the scope of the invention include an inert carrier and a compound of formula (I"), its pharmaceutically acceptable acid addition salts and/or its possible stereochemically isomeric forms and/or its possible A composition comprising an antivirally effective amount of a tautomeric form.

Among the new compound group, A! is the formula (, b-1), where B
4-C is a divalent group of aryl, pyridinyl, pyrimidinyl, lower alkyloxycarbonyl, aryl lower alkyl, diaryl lower alkyl, quinolinyl, or A! is formula (C), where R11 is hydrogen, aryl, arylamino, (aryl)(lower alkyl)amino, hydroxy, indolyl, and R6 is hydrogen, aryl, arylcarbonyl, (arylcarbonyl)lower alkyl is a divalent group of , or A! A compound of formula (■") in which is a divalent group of formula (d) is preferred.

Particularly preferred novel compounds are those in which the divalent group A2 is as defined for the preferred novel compounds, and R2 and R
This is a compound in which both of 3 are hydrogen.

Further particularly preferred compounds are those in which l(2,)j3 and A2 are as defined for particularly preferred compounds;
In the divalent group A2 having the formula Φ) m is an integer 2 or 3 and n is 2; in the group A2 having the formula (C) m is an integer 1 or 2 and n
is an integer 2, m is an integer 1 or 2, and n is an integer 2 in group A2 of formula (d).

Particularly preferred novel compounds are those in which Bt, Rs, At, m and n are as defined for the more particularly preferred novel compounds already mentioned, and R1 is halo, lower alkyloxy, aryloxy, lower alkylthio, These are arylthio and cyano compounds.

More particularly preferred new compounds are -Ba, Ba, A'',
More particularly preferred are compounds in which m and n are as defined for the novel compounds already mentioned and R1 is halo.

The most preferred compound within the scope of the invention is 3-bromo-6
-(4-(3-methylphenyl)-1-piperazinyl,
Selected from the group consisting of 3-chloro-6-[3,6-cyhydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine and pharmaceutically acceptable acid addition salts thereof.

Certain of the compounds of the present invention may have several asymmetric centers in their structural formulas. Pure stereoisomeric forms of compounds of formula (I) can be obtained by separation methods known in the art. For example, diastereomers can be separated by applying fractional crystallization or chromatographic methods, while enantiomers can be separated by fractional crystallization of their diastereomeric salts with optically active acids.

Pure stereoisomeric forms can be obtained by stereospecific synthesis starting from the corresponding stereochemically pure forms of appropriate starting materials. Stereochemical isomers of the compounds of formula (I) are intended to be encompassed within the scope of this invention.

The following examples are illustrative of the invention and are not intended to limit the scope of the invention in all its respects.

Unless otherwise specified, all parts in the examples are parts by weight.

Examples Example 1 221 parts of 4-fluorobenzeneacetonitrile, 30%
A mixture of 700 parts of sodium methylate solution and 900 parts of dimethylbenzene was stirred for 5 minutes. Next, 309 parts of methyl propionate was added dropwise (exothermic reaction: the temperature was 65°C).
). After the addition was complete, stirring was continued at reflux temperature overnight. Methanol was removed until the internal temperature was 110°C. After cooling, 100 parts of 6N hydrochloric acid solution were added dropwise and the whole was stirred and refluxed for 5 minutes. Upon cooling, the layers were separated. The organic phase was dried, filtered and evaporated. The residue was stirred and refluxed for 4 hours with 500 parts of acetic acid, 500 parts of water and 500 parts of hydrochloric acid solution.

After cooling, the product was extracted with trichloromethane.

The extract was washed successively with water, dilute sodium hydroxide solution and water again until neutral, dried, filtered and evaporated. The residue was crystallized from 2-glopanol and 1-(
134.5 parts of 4-fluorophenyl)-4-oxocyclohexanecarbonitrile were obtained; melting point 91.8°C (Intermediate 1).

Example 2 A mixture of 17.6 parts of 1-(phenylmethyl)piperazine, 8.4 parts of ethyl 4-fluorobenzoate and 45 parts of N,N-dimethylacetamide was stirred and refluxed for 22 hours. The reaction mixture was cooled and poured into 500 parts of water. The product was extracted three times with benzene. The combined extracts were washed three times with copious amounts of water, dried, filtered and evaporated.

The residue was stirred in hexane. The product was separated, washed with hexane and dried under vacuum to yield 12.5 parts (77%) of ethyl 4-(4-(phenylmethyl)-1-piperazinyl]benzoate (Intermediate 2). .

Example 3 14 parts of ethyl 4-(methylamino)-1-piperidinecarboxylate, 1 part of (3-chloro-1-propenyl)benzene
3 parts, 26.5 parts of I-IJium carbonate, and 4-methyl-
A mixture of 24 (l) of 2-pentanone was stirred and refluxed over the weekend using a water separator. The reaction mixture was cooled, water was added and the layers were separated. The organic phase was dried, filtered and and evaporated. The residue was converted to the ethanedioate salt in 2-gropanol and 2-propanone. The salt was taken apart, dried and 4-[methyl-(3-phenyl-2-propenyl)amino:] -]1-Piperidinecarboxylic acid E)-ethylethanedioate (1:1)23.
4 parts were obtained; melting point 160.2°C (intermediate 3).

Example 4 19 parts of 1-(phenylmethyl)-4-piperisinol,
One part of benzoyl chloride was added to a stirred mixture of 15.2 parts of N,N-diethylethanamine and 180 parts of methylbenzene.
4 parts were added dropwise (gradually).

After the addition was complete, stirring was continued for 3 hours at room temperature. The resulting hydrochloride of benzoyl chloride was separated and washed with methylbenzene. The filtrate was evaporated. The oily residue was purified on silica gel with a mixture of trichloromethane and methanol (9
It was purified by column chromatography using a 5:5 volume ratio).

The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. This product was separated in a furnace and dried to obtain 18 parts (54 parts) of [1-(phenylmethyl)-4-piperidinyl]benzoate hydrochloride; melting point 225.9°C (Intermediate 4).

Example 5 A solution of 11.7 parts of benzeneacetonitrile in 45 parts of methylbenzene was added dropwise at 25° C. to a stirred mixture of 7.8 parts of 5-tin sodium amide and 135 parts of methylbenzene in benzene (cooling required). did). 30 at 30℃
After stirring for a minute, 24.0% ethyl]-(phenylmethyl)-4-piperidinecarboxylate in 45 parts of methylbenzene.
7 parts of the solution were added dropwise at 30°C. After the addition is complete, stir for 8 minutes.
This was continued overnight at 0°C. Cool the reaction mixture and add ethanol 1
Two parts were added and the whole was poured into ice water. The layers were separated and the aqueous phase was neutralized with acetic acid. The oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone to give α-[
12 parts of hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]benzeneacetonitrile (3E
l); melting point 191.9°C (intermediate 5).

To 200 parts of water was carefully added 200 parts of acetic acid with stirring and cooling. Next, 368 parts of sulfuric acid was added dropwise (gradually). α-[Hydroxy[1-(phenylmethyl)-4-
Piperidinyl]methylidene]benzeneacetonitrile 9
0 parts were added and the whole was stirred and refluxed overnight. The acetic acid was evaporated and the residue was poured into crushed ice. The mixture was made alkaline with concentrated ammonium hydroxide and the oily product was extracted with trichloromethane. The extract was dried, filtered, and evaporated to leave a residue of 79 parts of 2-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]ethanone (96.3%
) was obtained (Intermediate 6).

Example 6 N-(2-chloroethyl)-N-(3-chloropropyl)-4-methylbenzenesulfonamide 93 parts, 2.3
A mixture of 30.3 parts of dimethylbenzenamine, 63.6 parts of sodium carbonate, 1 part of potassium iodide and 240 parts of cyclohexanol was stirred and refluxed over the weekend using a water separator. After cooling, the reaction mixture was poured into water.

The product was extracted with methylbenzene. The extract was washed twice with water, dried, filtered and evaporated. 2 residues
- Crystallized from propatool and a small amount of tetrahydrofuran. The product was separated and dried to 11.1-(2,3-dimethylphenyl), +Sabidro 4-((4-methylphenyl)sulfonyl)-IH-1,4-diazepine 47
．． 8 parts (53.3 parts) were obtained; melting point 86.2°C (intermediate 7).

In a similar manner, the following were also prepared;
2-methoxy-5-(+-lifluoromethyl)phenylcopiperazine hydrochloride; melting point 226.8°C (compound 8); 1-[(4-methylphenyl)sulfonyl]-4-(2
,4,6-1-dimethylphenyl)piperazine (Intermediate 9); 1-(3,5-';dichloroenyl)hexahydro-4
-[(4-methylphenyl)sulfonyl]-IH-1.
4-Diazepine (intermediate 10); 1-(3-10lofenyl)hexahydro-4-[(4-methylphenyl)sulfo,yl]-1H-1,4-diazepine; melting point 116
．． 6°C (intermediate J1); hexahydro-1-(2-methoxyphenyl)-4-(
(4-methylphenyl)sulfonyl]-IH-1.4-
diazepino, as residue (intermediate 12); and hexahydro-1-((4-methylphenyl)sulfonyl)-4-[3-(trifluoromethyl)phenyl]-
tH-1,4-diazepino, as residue (intermediate 13)
.

Example 7 1-[(4-methylphenyl)sulfonyl]-4-(2
,'4,6-1-limethylphenynolipiperazine 180
675 parts of sulfuric acid were added dropwise to a stirred mixture of 50 parts and 450 parts of water. The whole was stirred and refluxed for 5 hours. After cooling, the whole was treated with ammonium hydroxide solution. The product was extracted with dichloromethane. Dry the extract, filter,
Evaporation gave 70 parts (69%) of 1-(2,4,6-1 methylphenyl)piperazine as a residue (Intermediate 14
).

In a similar manner, the following were also prepared: =4-(
3-Methylphenyl)-4-piperidinecarboxamide (intermediate 15); 1-(2,3-dimethylphenyl)hexahydro-IH
-1,4-diazepine as residue (intermediate 16); hexahydro-1-(2-methoxyphenyl)-IH-
1,4-diazepine-hydrochloride; mp 176, 6°C (intermediate 17); and hexahydro-1-[3-(trifluoromethyl)phenyl]-LH-1,4-diazepine-hydrochloride; mp 19
1.1°C (intermediate 18).

Example 8 A mixture of 7.9 parts of ethyl 3-oxo-1-pyrrolidinecarboxylate, 5.35 parts of 3-methylbenzenamine, 1 part of 4% thiophene solution in methanol and 200 parts of methanol was supported on charcoal. Hydrogenation was carried out at normal pressure and 50° C. using 2 parts of a 10% haladium catalyst. After absorbing the calculated amount of hydrogen, the catalyst was separated and the p-liquid was evaporated to obtain 12.4 parts (100%) of ethyl 3-[(3-methylphenyl)amine-1-pyrrolidinecarboxylate as a residue ( Intermediate 19).

In a similar manner, the following were also prepared: N-(
2,3-dimethylphenyl)-1-(phenylmethyl)
-3-piperidineamine ethanedioate (1;l);
Melting point 151.6°C (intermediate 20): N-phenyl-1-(phenylmethyl)-a-piperidinamine, as residue (intermediate 21); 3-[(2,3
-dimethylphenyl)amine to ethyl 1-pyrrolidinecarboxylate as residue (intermediate 22); 4-[C3-(1-lifluoromethyl)phenyl]amine]-1-piperidinecarbonate to hydrochloride (intermediate 23)
); N-(3-methylphenyl)-1-(phenylmethyl)
-3-piperidinamine, residue (intermediate 24);
and ethyl 3-[:[3-(+-IJ-yfluoromethyl)phenyl]amine]-1-pyrrolidinecarboxylate as residue (Intermediate 25).

Example 9 To a stirred solution of 152 parts of 3-methyl-1-(phenylmethyl)-4-piperidinone in 900 parts of methylbenzene was added dropwise at room temperature 218 parts of ethyl carboxchloridate. After the addition was complete, stirring was continued under reflux overnight. After cooling, the reaction mixture was washed with water and hydrochloric acid, dried, filtered,
and evaporated. The residue was distilled to give 120.5 parts (83 parts) of ethyl 3-methyl-oxo-1-piperidinecarboxylate.
%); boiling point 98-105°C/1w pressure (intermediate 26
).

Example 10 1-(phenylmethyl)- is added to a stirred and refluxing Grignard complex previously prepared starting from a mixture of 4.2 parts of 1-bromo-3-chlorobenzene, 5.4 parts of magnesium and 135 parts of tetrahydrofuran. 19 parts of 3-piperidinone were added dropwise. After the addition was complete, stirring was continued for 1 hour at reflux temperature.

After cooling, the reaction mixture was poured into 2.5 parts of ice water and acetic acid. The layers were separated. The aqueous phase was extracted with trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanol.

This salt is taken from house to house, dried, and 3-(3-chlorophenyl)
26 parts (76%) of -1-(phenylmethyl)-3-piperiditul hydrochloride were obtained (Intermediate 27).

In a similar manner, the following was also prepared: ethyl 4-hydroxy-4-(2-chenyl)-1-piperidinecarboxylate; mp 146.2°C (intermediate 28): 4-hydroxy-4-( Ethyl 1-naphthalenyl)-1-piperidinecarboxylate: Melting point 109.2-114.8
(Intermediate 29); ethyl 3-[4-chloro-3-(trifluoromethyl)phenyl-3-hydroxy-1-pyrrolidinecarboxylate as residue (Intermediate 30); 4-hydroxy-4-
Ethyl (2-naphthalenyl)-1-piperidinecarboxylate as residue (intermediate 31); 3-(3-methylphenyl)-1-(phenylmethyl)
-3-piperiditul hydrochloride (intermediate 32); cis-3-methyl-4-(3-methylphenyl)-1-
(phenylmethyl)-4-piperiditur, as a residue (intermediate 33); ethyl cis-4-(3-fluorophenyl)-4-hydroxy-3-methyl-1-piperidinecarboxylate, as a residue (intermediate 34); Ethyl cis-4-hydroxy-3-methyl-4-(2-chenyl)-1-piperidinecarboxylate, as a residue (35); 3-hydroxy-3-(2-chenyl)-1-piperidinecarboxylate Ethyl acid (intermediate 36); 3-(3-fluorophenyl)-1-(phenylmethyl)-3-piperiditur hydrochloride (intermediate 37); 4-(2,3-dimethylphenyl)-4-hydroxy-
Ethyl 1-piperidinecarboxylate (intermediate); 3-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperiditul hydrochloride (intermediate 39); 3=(3-methylphenyl)-1 -(phenylmethyl)
3-( 3-fluorophenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride (intermediate 42); 4-hydroxy-4-(3-methoxyphenyl)-3-
Ethyl methyl-1-piperidinecarboxylate as a residue (intermediate 43); and 3-(3-7'toxyphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride (intermediate 44).

Example 11 A mixture of 7 parts of 3-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperiditur hydrochloride and 200 parts of 6N hydrochloric acid solution was stirred and refluxed overnight. The reaction mixture was evaporated.

Water was added and the base was liberated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as eluent. The first fraction was collected, the eluent was evaporated, and the residue was 5-(2,3-dimethylphenyl)-1,2,3,4-tetrahydro-1
-(Phenylmethyl)pyridine 0.7s (12th) was obtained (Intermediate 45). The second fraction was collected and the eluent was evaporated, leaving a residue of 5.3 parts of 5-(2°3-dimethylphenyl)-1,2,3,6-titrahydro-1-(phenylmethyl)pyridine (91% ) was obtained (intermediate 4
6).

Example 12 3-(3-methylphenyl)-1-(phenylmethyl)
-8 parts of 3-pyrrolidinol hydrochloride and 15 parts of 6N hydrochloric acid solution
0 parts of the mixture was stirred and refluxed for 3 hours. After cooling,
The reaction mixture was evaporated and the residue was 2,3-dihydro-
4-(3-methylphenyl)-1-(phenylmethyl)
7.4 parts (100 parts) of -1H-pyrrole hydrochloride were obtained.

In a similar manner also prepared: 1.2
,3.6-titrahydro-5-(3-methylphenyl)
-1-(phenylmethyl)pyridine, as a residue (intermediate 48); and 5-(3-fluorophenyl)-1,2,3°6-titrahydro-1-(phenylmethyl)pyridine hydrochloride (intermediate 49) .

Example 13 3-(3-/70 phenyl)-1-(phenylmethyl)-3-piperiditul in 270 parts of methylbenzene 1
10.9 parts of ethyl carboxloridate were added dropwise to 3 parts of the stirred solution at room temperature. After the addition was complete, stirring was continued at reflux temperature overnight. After cooling to room temperature, the whole was washed with water and hydrochloric acid. The organic layer was dried, filtered and evaporated leaving 3-(3-chlorophenyl)-3-hydroxy-1 as a residue.
-7 parts (58%) of ethyl piperidine carboxylate were obtained (
Intermediate 50).

Example 14 A mixture of 11.8 parts of N-(2,3-dimethylphenyl)-1-(phenylmethyl)-3-piperidinamine and 120 parts of methanol was prepared using 2 parts of a 10% palladium catalyst supported on charcoal. Hydrogenation was then carried out at normal pressure and room temperature.

After absorbing the calculated amount of hydrogen, the catalyst is
1) to evaporate the F solution. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99:1 to 95:5 volume ratio) as eluent. The pure flank John was collected and the eluent was evaporated. The residue was converted to ethanedioate in 2-propanol and 2-prono(N). The salt was separated, dried and converted to N-(2,3-dimethylphenyl)-3-piperidinamine ethanedioate (1 :1) 7 parts (79.5 parts) were obtained. Melting point: 161.
6°C (intermediate 51).

In a similar manner to the above, the following was also prepared: Ethyl 4-(1-piperidinyl)benzoate; mp 10
2.6°C (Intermediate 52); Benzoic acid (4-piperidinyl) hydrochloride; Melting point 236.8
°C (intermediate 53); N-phenyl-3-piperidinamine; melting point 79.8 °C
(Intermediate 54); N-(3-methylphenyl)-3-piperidinamine,
as residue (intermediate 55); 4-[(3-methylphenyl)aminoco-4-piperidinecarboxamide, as residue (intermediate 56); 2-phenyl-1-(4-piperidinyl)ethanone hydrochloride; Melting point 198.6°C (intermediate 57); 3-(3-methylphenyl)piperidiyne, residue (intermediate 58)
; 3-(3-methylphenyl)-3-piperiditur hydrochloride (intermediate 59); cis-3-methyl-4-(3-methylphenyl)-4-
Piperiditool, as residue (intermediate 60); 3-(3
-fluorophenyl)-3-piperiditur hydrochloride (intermediate 61-): 3-(2,3-dimethylphenyl)-3-piperiditur hydrochloride aqueous solution; melting point 135.5°C (intermediate 62); 3- (2,3-dimethylphenyl)piperidine as residue (intermediate 63); 3-(3-methylphenyl)-3-pyrrolidinol (intermediate 64); 3-(3-methoxyphenyl)-3-piperiditul hydrochloride , as a residue (intermediate 65); 3-(3-fluorophenyl)-3-pyrrolidinol as a residue (intermediate 66); and 3-(3-methoxyphenyl)-3-pyrrolidinol as a residue (intermediate body 67).

Example 15 A mixture of 13.10 parts of ethyl 3-[(2,3-dimethylphenyl)aminoco-1-pyrrolidinecarboxylate, 28 parts of potassium hydroxide and 240 parts of 2-propatol was stirred and refluxed for 6 hours. . The reaction mixture was evaporated. The residue was added to lζ of water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated to give a residue of 6 parts (63%) of N-(2,6-dimethylphenyl)-3-pyrrolidinamine (Intermediate 68).

In a similar manner, the following were also produced = (E)
-N-methyl-N-(3-phenyl-2-propenyl)
-4-Piperidine dihydrochloride hemihydrate; melting point 240.2°C
(Intermediate 69); N-C3-(trifluoromethyl)phenyl]-4-piperidinamine hydrochloride; melting point 253.2°C (Intermediate 70
); N-(3-methylphenyl)-3-pyrrolidineamine ethadioate (l:2); melting point 180°C (intermediate 71)
; 4-(2-chenyl)-4-piperiditul; melting point 14
5.9°C (intermediate 72); 4-(1-naphthalenyl)-4-piperiditul; melting point 185.1-187.8°C (intermediate 73); 3-C4-
Do-3-(1-lifluoromethylphenyl]-3-pyrrolidinol; M point t 38.4-142.1°C (intermediate 74); 4-(2-naphthalenyl)-4-piperiditul (intermediate 75); N-[3-(trifluoromethyl)phenyl]-3-pyrrolidineamine dihydrochloride (intermediate 76): cis-4-(
3-fluorophenyl)-3-methyl-4-piperidinyl, as residue (intermediate 77); cis-3-methyl-4-(2-chenyl)-4-piperiditur, as residue (intermediate 78): 3 -(2-chenyl)-3-piperidino JL/(intermediate 79); 3-(3-chlorophenyl)-3-piperisinol hydrochloride (intermediate 80); 4-(2,a-dimethylphenylliditur) (intermediate 4-(3-chlorophenyl)-3-methyl-4-piperiditul, as residue (intermediate 82); 3-[4-10
Rho 3-(1-lifluoromethylphenyl-3-piperiditur (intermediate 83); and 4-(3-methoxyphenyl)-3-methyl-4-piperiditul as the residue (intermediate 84).

Example 16 A mixture of 3 parts of 3-(3-fluorophenyl)-3-pipe IJ,)nol hydrochloride and 100 parts of 6N hydrochloric acid solution was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was taken up in water and ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated to give a residue of 22 parts (96%) of 5-(3-fluorophenyl)-1,2,3,6-titrahydropyridine (intermediate body 85).

Following the same method and using equivalent amounts of the appropriate starting materials, the following was also prepared: 4-[4-chloro-3-(trifluoromethyl)phenyl)-1,2,3,6-titrahydro Pyridine hydrochloride (
Intermediate 86): 1.2,3.6-titrahydro-4-(2-chenyl)
Pyridine hydrochloride (intermediate 87); 1,2,3,6-titrahydro 4-[:3-(trifluoromethyl)phenylcopyridine as residue (intermediate 88); 1,2,3,6-titrahydro 4-(l-naphthalenyl)pyridine hydrochloride; melting point 277.5°C (intermediate 89)
1,2,3,6-titrahydro-5-(3-methylphenyl)pyridine hydrochloride (intermediate 9o); 3,4-dihydro-3-(2-thenyl)-1H-pyrrole as residue (intermediate 91); and 3-(2-chenyl)pyrrolidine as residue (intermediate 92).

Example 17 5-(3-fluorophenyl)-1,2,3°6-titrahydro l-(phenylmethyl)pyridine hydrochloride6.
A mixture of 5 parts and 120 parts of methanol was heated at normal pressure and 50 parts using 1 part of 10% palladium on charcoal catalyst.
Hydrogenated at °C. After absorbing the calculated amount of hydrogen, the catalyst was removed and the lachrymal fluid was evaporated, yielding 4.5 parts (100%) of 3-(3-fluorophenyl)piperidine hydrochloride as a residue (Intermediate 93).

In a similar manner, the following were also prepared: =4-(
2-chenyl)piperidine hydrochloride (intermediate 94); and 3-(3-methylphenyl)pyrrolidine hydrochloride as residue (intermediate 95).

Example 18 N-(3-methylphenyl)-1-(phenylmethyl)
-21 parts of 4-piperidinamine hydrochloride, 9 parts of poly(oxymethylene), 15 parts of potassium acetate, 4 parts in methanol
A mixture of 2 parts of a solution of % thiophene and 200 parts of methanol was hydrogenated at atmospheric pressure and room temperature using 4 parts of a 10% palladium catalyst on charcoal. After absorbing the calculated amount of hydrogen, the catalyst was furnace-separated on the hyphen and the F liquid was evaporated.

From the residue, the free base f-j was prepared by ammonium hydroxide.
h first blue book Sn/y1ffir*J force 1 no 1 talk seven mountain 1
The town also dried the mountains, dried them, and evaporated them.

The residue was purified on silica gel using a mixture of trichloromethane and methanol (99:1 ratio) as eluent.
Purified by column chromatography.

The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. This salt was taken from house to house and dried to obtain 2.4 parts (75%) of N-methyl-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinamine dihydrochloride hemihydrate. Melting point: 201.3°C (Intermediate 96).

A mixture of 9 parts of N-methyl-N-(3-methylphenyl)-z-(phenylmethyl)-4-piperidinamine dihydrochloride hemihydrate and 200 parts of methanol was prepared using a 10% palladium catalyst supported on charcoal. Two parts were hydrogenated at normal pressure and room temperature. After absorbing the calculated amount of hydrogen, place the catalyst on the hood and place it on the 51st L-. It was converted to the hydrochloride in 1. This salt was separated and dried to obtain 1.5 parts (60.9 parts) of N-methyl-N-(3-methynophenyl)-4-piperidinamine dihydrochloride hemihydrate; melting point 209 .1°C (intermediate 97).

B. Preparation of the final compound Example 19 A mixture of 47.6 parts of 1H-imidazole, 33.6 parts of 50% sodium hydride dispersion and 750 parts of N,N-dimethylformamide was stirred at room temperature for 15 minutes. The resulting solution was dissolved in 750 parts of N,N-dimethylformamide.
-106 parts of dichloropyridazine and the whole was stirred for a further 2 days at room temperature. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from methanol. The product was separated off, washed with petroleum ether and dried to give 48.5 parts of 3-chloro-6-(IH-imidazol-l-yl)pyridazine; melting point 182.9°C (compound 1).

Example 20 A mixture of 3 parts of 3.5-dimethylphenol, 1.25 parts of 50% sodium hydride dispersion and 25 parts of N,N-dimethylformamide was stirred for 15 minutes. Then 3-chloro-6-(l) in 25 parts of N,N-dimethylformamide
A solution of 4.5 parts of I-imidazol-1-yl)pyridazine was added and the whole was stirred at 50°C over the weekend. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanone to give 3-(3,5-dimethylphenoxy)-6-(tH-imidazol-1-yl).
3.5 parts of pyridazine were obtained: melting point 169.8°C (compound 2).

In a similar manner, also prepared: 3-(
IH-imidablue 1-yl)-6-(4-methylphenoxy)pyridazine; melting point 146.8°C (compound 3).

3-(IH-imidazol-l-yl)-6-(3-nitrophenoxy)pyridazine: melting point 171.5°C (compound 4); and 3-(4-chlorophenoxy)-6-(l)l-imidazole -yl)pyridazine; melting point 165.8°C (Compound 5).

Example 21 A mixture of 4.5 parts of 3-chloro-6-(IH-imidazol-1-yl)pyridazine, 3.2 parts of 4-bromophenol, 4.2 parts of sodium charcoal, and 80 parts of 2-prono(non) was stirred and refluxed over the weekend. The reaction mixture was evaporated and the residue was taken up in water and 2,2'-oxybispronochloride. The layers were separated. The organic phase was dried and
Filter and steam vc, >0-a-Tdl wide f-Q-
Pn) Kuno J 6) C1 Horoku → To-3-(4-bromophenoxy)-6-(IH-imidazol-1-yl)
3.5 parts of pyridazine were obtained; melting point 168.4°C (compound 6).

Example 22 4.35 parts of 1-(4-fluorophenyl)-4-oxycyclohexanecarbonitrile, 3.3 parts of 1-(3-piperazinyl)pyridazine, 0.2 part of 4-methylbenzenesulfonic acid, and 360 parts of methylbenzene The mixture was stirred and refluxed overnight using a water separator. The reaction mixture was cooled and evaporated leaving 1-(4-fluorophenyl)-4-C4-(3-pyridazinyl)-1-piperazinyl]-3-cyclohexanecarbonitrile7.
3 parts (100%) were obtained (compound 7).

Stirring of 7.3 parts of 1-(4-fluorophenyl)-4-[4-(3-pyridazinyl)-1-piperazinyl]-3-cyclohexanecarbonitrile, 1 part of 30 tin sodium menate bath solution, and 240 parts of methanol. 0.8 part of sodium borohydride was added in portions to the resulting mixture. After the addition was complete, stirring was continued at room temperature overnight. The reaction mixture was poured into ice water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2=glopanol and 1-(4-fluorophenyl)
4.5 parts (61.5 units) of -4-C4-(3-pyridazinyl)-1-piperazinylcocyclohexanecarbonitrile were obtained; melting point 188.7°C (compound 8).

Example 23 3.1 parts of 6-dichloropyridazine, 3 parts of 1-(2-fluorophenyl)piperazine, 3.2 parts of sodium carbonate
A mixture of 1 part, 0.1 parts of potassium iodide and 72 parts of N,N-dimethylformamide was stirred over the weekend and
Heated to 0°C. The reaction mixture was poured into water. The precipitated product was separated from P and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by filtration on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as dissociating agent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propatol and 2,2'-oxybispropane to give 3-chloro-6
4.5 parts (77%) of -(4-(2-fluorophenyl)-1-piperazinyl)pyridazine were obtained; melting point 148.
0°C (Compound 9).

Following a similar method and using equivalent amounts of the appropriate starting materials, the following was also prepared: Example 24 3,6-difluoropyridazine 2.7s, 1-[3-(
A mixture of 4.6 parts of 1-lifluoromethyl) or enyl]piperazine, 3.2 parts of sodium carbonate, and 90 parts of N,N-dimethylformamide was stirred at 60°C overnight. The reaction mixture was poured into water. The product is taken from house to house, washed with water, and 2-
Crystallized from glopanol to give 3-fluoro-6-[4-
3 parts (46%) of C3-()lifluoromethyl)phenyl]-1-piperazinyl]pyridazine were obtained: mp 131
．． 5°C (compound 24).

In a similar manner, the following were also prepared: =3-[
4-(2,3-dimethylphenyl)-1-piperazinyl-6-fluoropyridazine; melting point 144.1°C (compound 25); 3-fluoro-6-[4-(3-methylphenyl)-1
-piperazinyl]pyridazine: melting point 128.1'c (chemical &wJ26); and 3-[3,6-sihydro4-(3
-methylphenyl)-1(2H)-pyridinyl]-6-
Fluoropyridazine: Melting point 105.2°C (Compound 27)
.

Example 25 3.6-dichloropyridazine 4.5 parts, l, 2°3.6
A mixture of 5.2 parts of -titrahydro-4-(3-methylphenyl)pyridine, 5.3 parts of sodium carbonate, and 72 parts of N,N-dimethylformamide was stirred overnight and
heated to ℃. The reaction mixture was evaporated and water was added to the residue. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residual liquid was crystallized from 2-gropanol. The product was separated and dried to obtain 2.1 parts (24 parts) of 3-chloro-6-[3,6-sihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine; Melting point 122.
2°C (compound 28).

Following a similar method and using equivalent amounts of the appropriate starting materials, the following was also prepared: Example 26 5 parts of 1-(3-methylphenyl)biperazine dihydrochloride,
A mixture of 10.6 parts of sodium carbonate and 180 parts of N,N-dimethylformamide was stirred at 65°C for 1 hour. Next, 72 parts of 3,6-dipromoviridazine were added and the whole was stirred at about 65°C overnight.

The reaction mixture was poured into ice water. The product was filtered off and dissolved in dichloromethane. The solution was washed twice with water, dried, oven and evaporated. The residue was crystallized from ethanol. The product was filtered and dried to give 4.1 part (61.5 part) of 3-promo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine (61.5 part); melting point 14.
5.7°C (Compound 136).

In a similar manner, 3-promo 6-(4-(2,5-dimethylphenyl)-1-
Piperazinyl]pyridazine: melting point 166.7°C (compound 137); 6-bromo6-[4-(3-chlorophenyl)-1-
piperazinyl]pyridazine; melting point 15a7℃ (compound 1
38): 3-bromo6-[4-(3-)lifluoromethyl)phenyl]-1-piperazinyl]hyridazine; melting point 154
．． 3°C (compound 139): 6-bromo 6-(4-(2
-methoxyphenyl)-1-piperazinyl]pyridazine; melting point 164.8°C (compound 140): 3-bromo6-[4-(3-trifluoromethyl)phenyl-1-piperidinyl]pyridazine-hydrochloride; melting point 154. 3°C (compound 141); 3-bromo 6-(
3,6-Sihydro-4-[3-()IJfluoromethyl)phenyl)-1(2H)-pyridinyl]pyridazine:
Melting point 130.6°C (Compound 142): 1-(6-bromo 3-pyridazinyl)-4~<5-chlorophenyl)hexahydro-IH-1,4-diazepine; Melting point 14a8°C (Compound 143): 3-bromo 6-(4-(3-bromophenyl)-1-
piperazinyl]pyridazine; melting point 1798°C (compound 1
44): and 3-bromo-6-[3,6-cyhydro-4-(3-methylphenyl)-1XK(2/7)-pyridinyl]pyridazine; melting point 1211°C (compound 145).

Example 27 4.5 parts of 3.6-dichloropyridazine, A'-(3-(
A mixture of 4.9 parts of IJ fluoromethyl)phenyl]-5-piperidinamine, 6.4 parts of sodium carbonate, and 180 parts of N,N-dimethylformamide was stirred at about 65°C overnight. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99:1 volume ratio) as eluent.

The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-pro/zonol. Separate the product (separate P solution), dry, and prepare 1-(6-chloro-5-pyridazinyl)-N-C3-()IJfluoromethyl)phenyl)-3-piperidinamine 1.2 Part (1
6,8i was obtained; melting point 92.6°C (compound 146). The ν solution set aside was converted to the hydrochloride salt in 2-propertool. This salt was separated from P, dried, 1-(6-chloro-6
-pyridazinyl)-N-C5-()lifluoromethyl]
2.6 parts of -3-piperidinamine hydrochloride (32.9 parts) were obtained; melting point 173.5°C (compound 147).

Example 28 76 parts of 5.6-cyclopyridadi, 6.1 parts of #-[3-(trifluoromethyl)phenyl]-4-biperidinamine dihydrobromide, 6.4 parts of sodium carbonate and N,
A mixture of 180 parts of N-dimethylacetamide was stirred at 60°C for 24 hours.

After cooling to room temperature, the reaction mixture was poured into water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97:3 volume ratio) as eluent. Collect pure fractions,
The eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was separated by F, dried and 1-(
6-chloro-5-pyridazinyl/V-(3-(trifluoromethyl)phenyl]-4-biveridinamine 2,
5 parts (47 liters) were obtained; melting point 1119°C (compound 148
).

Following a similar method and using equivalents of the appropriate starting materials, the following was also prepared: Example 29 52 parts of 3,6-soiodopyridanone, 1-[3-(trifluoromethyl)phenylcopiperazine A mixture of 3.5 parts, 3.2 parts of sodium carbonate, and 90 parts of N,N-dimethylacetamide was stirred and heated to 70°C overnight. The reaction mixture was poured into water.

The precipitated product was filtered and crystallized from 2-7' lovanol to yield 3-iodo-6-(4-[3-()lifluoromethyl)phenyl]-1-piverasonyl]viridason3.
2 parts (48 portions) were obtained; melting point 144.6°C (compound 20
2).

In a similar manner, the following was also prepared: 6-iodo-6-[4-(3-methylphenyl)-1-piperazinyl]viridason; melting point 163.1°C (compound 203
): 3-(4-(3-chlorophenyl)-1-piperazinyl 1-6-iotopyridazone: Melting point 1A5-n°C (Compound 204): 3-[4-(2,3-tumethylphenyl)-1-piperazinyl ]-6-Iotopyridazone; melting point 179, 4°C
(Compound 205): and 6-yotho6-[4-[3-
()Lifluoromethyl)phenyl]-1-biperizonyl]viridason; melting point 106.8°C (Compound 206).

Example 30 4.6 parts of 1-[3-(trifluoromethyl)phenyl]hyherazine, 6.4 parts of sodium carbonate and 4-methyl-
A mixture of 7,277,160 parts of 2-pe was dried by azeotropic distillation. 6.3 parts of 6-sochloropyridanone were added and the whole was stirred and refluxed for 48 hours using a water separator. After cooling, water was added and the product was extracted with sochloromethane. The organic layer was dried, filtered and evaporated.

The residue was purified on silica gel using a mixture of trichloromethane and methanol (99:1 volume ratio) as eluent.
Purified by column chromatography. Collect the pure fractions and evaporate the eluent. The residue was crystallized from 2-gropanol and 3-chloro-6-[4-(3
-()Lifluoromethyl)phenyl]-1-piperazinyl]pyridazine 2.6 parts (5Z9 excellent) was obtained; melting point 14
9.4°C (Compound 207).

Example 31 To a stirred solution of 5 parts of 6°6-cyclopyridanone Z in 75 parts of N,N-trimethylformamide are added 8 parts of ethyl 1-piperazinecarboxylate in 25 parts of N,N-trimethylformamide. and a solution of 56 parts of N,N-soethylethanamine was added dropwise.

After the addition was complete, the whole was stirred overnight at a temperature of about 50°C. After cooling, the reaction mixture was poured into water and the product was extracted with trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-glopanol to give 4-(6
3.6 parts of ethyl (chloro-3-pyridasonyl)-1-piperazinecarboxylate were obtained; melting point 123.8°C (compound 208).

Example 62 3-chloro-6-(methylsulfonyl)hiIJfdine 3
．． 21. 3 parts of 1-(3-methylphenyl)piperazine,
2 parts of N,N-noethylethanamine and 180 parts of benzene
The mixture was stirred under reflux for 24 hours. The reaction mixture was evaporated. Water was added to the residue. The precipitated product was separated, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from methanol. The product was filtered, dried and 6-[
4-(3-methylphenyl)-i-piperazinyl]-6
5 parts of -(methylsulfonyl)pyridazone (89 winters) were obtained; melting point 201°C (compound 209).

In a similar manner, the following were also prepared:
4-(3-methylphenyl)-1-piperazinyl)-6
-(methylsulfinyl)hyridazone; melt a116.9
°C (compound 210): 3-[3,6-sohydro 4-(
6-methylphenyl)l(2H)-pyridinyl')-6
-(methylsulfonyl)pyridazine: fi point 179.8
°C (Compound 211): and 3-, [3,6-sohydro-4-(3-methylphenyl)-1(2H)-pyridinyl)-6-(methylsulfinyl)viridason; melting point 131.0 °C (Compound 212)
.

Example 33 A mixture of 6.3 parts of 5.6-cycloviridanone, 3.3 parts of 1.1-(2-pyridinyl)piperazine, 1.5 parts of sodium bicarbonate, and 120 parts of ethanol was heated over a weekend. Watch? ? IF Rokuzeki-M Inn flood hardware was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99:1 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-gropanol and tetrahydro7ran, giving 3-chloro-6-(4-(2-pyridinyl)-1-
2.5 parts (45.3%) of piperidinyl]pyridazone were obtained; melting point 1947°C (compound 215).

Example 34 6.2 parts of 3-chloro-6-(methylthio)pyridazine,
1.2.3.6-titrahydro-4-(3-methylphenyl)virison hydrochloride 3.14 parts, sodium carbonate 5.
A mixture of 3 parts and 80 parts of r-m-1-butanol was bathed at reflux temperature for 48 hours. The reaction mixture was evaporated. Added water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-Glo-Gnol. The product was filtered, dried and 3-C3,6-
Sihydro-4-(3-methylphenyl)-1 (27/3
-Birisonyl]-6-(methylthio)pyridazine 0.8
(18'l): melting point 1298°C (compound 214
).

Example 35 Hexahydro-1#-1 in 900 parts of methylbenzene,
To a stirred solution of 300 parts of 4-soazepine was added 75 parts of 3,6-sochloropyridazine.

The whole was stirred and refluxed for 4 hours. The reaction mixture was evaporated. Water was added to the residue. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanol and ethanol. This salt was filtered, dried and 1-(6-chloro-3-pyridazinyl)hexahydro-IB-1,4
28 parts (22%) of -diazene hydrochloride was obtained (Compound 215).

In a similar manner, the following were also prepared: 1-(
6-chloro-5-methyl-5-pyridazonyl)hexahydro-IB-1,4-soazebin as residue (compound 216).

Example 36 3.6-dichloro-4,5-trimethylpyridazine 3.9
Part, 1-(2,3-dimethylphenyl)biperazone4.
A mixture of 2 parts and 2.94 parts of potassium carbonate was stirred and heated to 190°C in an oil bath for 4 hours. After cooling, the mixture was taken up in water and trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from 2-propertool. The product was separated in the oven and dried.
．． 2 parts of 3-chloro-6-[4-(2,3-dimethylphenyl)-1-biperasonyl]-4,5-somethylviridason (304) were obtained; melting point 194.5°C (compound 21
7).

In a similar manner, the following was also prepared: 5-chloro4.5-tmethyl-6-(4-(3-methylphenyl)-1-biperasonyl)viridason; mp 172.
9°C (Compound 218): and 4-(3-methylphenyl)-1-(6-methyl-5-pyridazinyl)-4-piperisonol; melting point 131.5°C (Compound 219).

Example '57 N-(6-chloro-3-pyridazinyl)acetamide 5
．． 5 parts, 1-(3-methylphenyl)bi 22f 6.6
160 parts of potassium carbonate and 28 parts of potassium carbonate in an oil bath.
The mixture was stirred at ℃ for 7 hours. After cooling, trichloromethane and water were added. The layers were separated.

The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (97:3 volume ratio) as eluent. A second fraction was collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-7''roAnor and 2-zolopanone. The salt was filtered off, dried and the 6-[4-(3-methylphenyl)
-1-piperasonyl]-3-pyridaso/amine dihydrochloride 0.5 part (6,6 section) was obtained; melting point 178.5°C (compound 220).

Example 38 A mixture of 4 parts of 6-chloro-3-(4-ethylphenoxy)pyridazone and 6 parts of 1-(3-methylphenyl)piperazine was stirred and heated to 110<0>C in an oil bath for 6 hours. The whole thing was left overnight.

Ti11 ammonium oxide and trichloromethane were added. The precipitate was separated, and the p-liquid was poured onto a silica gel using a mixture of trichloromethane and methanol (95%) as an eluent.
:5 volume ratio) and purified by column chromatography. The pure 7-lactone was collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispronone. The product was separated and dried to give 3-(4-ethylphenoxy).

1.7 parts (27%) of -6-(:4-<5-methylphenyl)-1-piperazinyl]viridason were obtained; melting point 10
6.6°C (Compound 221).

Following a similar method, using equivalent amounts of the appropriate starting materials,
We also manufactured the following:

3-Methyl-6-[4-(3-methylphenyl)-1-
piperasonyl]pyridazine; melting point 1529°C (compound 2
22): and 3-(4-(3-methylphenyl)-1-piperazinyl]-(S-(methylthio)pyridazine; melting point 14-5.
00G (compound 223).

Example 69 4-(6-chloro-5-methyl-6-pyridazinyl)-
A mixture of 22 parts of ethyl 1-piperazonecarboxylate, 28 parts of potassium hydroxide, and 160 parts of 1-tucunol was stirred at reflux temperature overnight. The reaction mixture 1 was evaporated and water was added. The product was extracted with trichloromethane. The extract was dried [7], filtered, and evaporated. 2. Added 2'-oxybispropane. The product is distributed door to door, dried, and 3-
17 parts (100 parts) of chloro-4-methyl-6-(1-piperazinyl)pyridazine were obtained (compound 224).

Example 40 A mixture of 6 parts of ethyl [1-<6-chloro d-3-gyridacinyl)-4-piperidinyl]carbamate and 60 parts of concentrated hydrochloric acid was stirred and refluxed for 24 hours. The reaction mixture was evaporated. Water was added and the whole was treated with concentrated ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried and evaporated to give 1-(6-chloro-6-
pyridazinyl)-4-piperidinamine 3.8 parts (82
1 was obtained; melting point 260°C (decomposition) (compound 225).

Example 41 A mixture of 3.6 parts of 3-chloro-6-(1-piperazinyl)pyridazine-hydrochloride, 5.3 parts of sodium carbonate, and 90 parts of N,N-trimethylacetamide was heated to 60°C and mixed in 7 parts <stirred did. Next, 5 parts of (3-bromopropyl)benzene were added and the whole was stirred at 60°C overnight. The reaction mixture was poured into water. The product was taken separately and converted to the hydrochloride salt in 2-propanol. This salt was filtered and dried to obtain 6-chloro-6-C4-(3-phenylglobyl)-1-biperasonyl]pyridazine-hydrochloride 3.29 (60%)'; melting point 20Z6°C (compound 226).

In a similar manner, the following were also prepared: :1)-hydrate; melting point 18Z2
°C (compound 227): 6-methoxy-6-(4-(3-
phenylzolovir)-1-biperazunyl] viridadun;
Melting point: 784°C (Compound 228): 3-[4-(3-phenylpropyl)-1-biperasonyl]pyridasonyl dihydrochloride-hydrate; Melting point: 209.0°C
(Compound 229): and 1-acetyl-4-(6-chloro-3-biligsonyl)piperazine; melting point 153.6°C
(Compound 230).

Example 42 A mixture of 75 parts of 3-chloro-6-(1-piperazinyl)pyridazole, 2 parts of benzene acetylaldehyde, 1 part of a quaternary solution of thiophene in methanol, and 200 parts of methanol was prepared as a 5-metal platinum catalyst supported on charcoal. Two parts were hydrogenated at normal pressure and room temperature. After absorbing the calculated amount of hydrogen,
The catalyst was separated from the furnace and the F liquid was evaporated. The residue was crystallized from 2-propatool. The product was taken apart and dried to yield 1.5 parts of 3-chloro-6-C4-<2-phenylethyl)-1-piperazinyl]pyridazone (331; mp 14
0.0°C (Compound 231).

In a similar manner, the following were also prepared: =5-(
4-Butyl-1-piperazinyl)-6-chloroviridason (E)-2-putensooate (1:1): melting point 18
a2°C (Compound 2321: 5-chloro-6-(4-cyclohexyl-1-piperazinyl)viridason: Melting point 18
12°C (Compound 233): and 1-(6-chloro-3-pyridazinyl)-N-(phenylmethyl)-4-piperidinamine; melting point 93.8°C (
Compound 234).

Example 46 A mixture of 4 parts of 1-(6-chloro-5-pyridazinyl)-4-(3-methoxyphenyl)-4-piperidinol, 80 parts of ethanol, and 50 parts of 6N hydrochloric acid solution was stirred at reflux temperature for 6 hours. The reaction mixture was evaporated. Add water;
The whole was treated with concentrated ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, PJ and evaporated. The residue was crystallized from 2-propatool. The product is taken from house to house, dried and 3-chloro-6-[3,
6-dihydro-4-(3-methoxyphenyl)-1(2
2.5 parts (part 64) of B)-pyrisonyl]pyridazine were obtained; melting point 126.4°C (compound 235).

Following a similar method and using equivalent amounts of the appropriate starting materials, also prepared: 3-chloro-6-C4-<5-chlorophenyl)-6,
6-duhydro1(2#)-virisonyl]viridason;
Melting point 133.9°C (compound 236): 3-chloro-6
-(3,4-dihydro-5-phenyl-1(2R)-pyrinonyl)HILJ dason; melting point 1460°C (compound 23
7); 5-chloro-643,4-dihydro-5-(3-methylphenyl)-1(2H)-virisonyl]viridason; melting point 160.0°C (compound 238): 3-chloro-6-(
4-(3-fluorophenyl)-3,6-dihydro-1
(2#)-pyridinyl]pyridazone; melting point 124.7°C
(Compound 239);3-chloro-6-[:4-(2,3
-trimethylphenyl)-3,6-dihydro-1(2H)
-Birisonyl]-pyridazone; melting point 144.2°C (compound 240); 6-chloro-6-(4-(3-chlorophenyl)-3,
6-sihydro-5-methyl-1(2B)-bilisonyl]
Viridason; melting point 885°C (compound 241): 5-chloro-6-[3,4-dihydro-5-[6-(toIJfluoromethyl)phenyl']-1(2H)-pyridinyl]viridason; melting point 1632° C (compound 242
): 6-chloro6-[3,6-dihydro-5-C3-(toIJfluoromethyl)phenyl]-1(2,Z/)-virisonyl]viridason; melting point 1125°C (compound 243
); 3-chloro-6-C5-(5-fluorophenyl)-3
,6-Shydro-1(2H)-bilisonyl]pyridazine; melting point 134.9°C (Compound 244): 6-chloro-6-[3,4-Sohydro-5-(3-methoxyphenyl)-1(2B)-pyridazine ]Pyridazine; melting point 129
1°C (Compound 245): 6-chloro-6-[5-(2,3-dimethylphenyl)
-3,4-sohydro-1(2B)-pyridinyl]viridason; melting point 148.8°C (compound 246); 5-chloro-6-(3,6-sohydro-4-(2-naphthalenyl)-1(2H)- [pyrisonyl] viridasone hydrochloride hemihydrate; melting point 18Z2°C (compound 247): 6-chloro-6-[3-(3-methylphenyl)-2E
-pyrrol-N5H)-yl]pyridazine; melting point 198.
1°C (compound 248); 3-chloro-6-[2,3-
dihydro-4-(3-methylphenyl)-1H-pyrrol-1-yl]viridason; melting point 195.3°C (compound 2
49):3-chloro-6-[3,6-sohydro4=(
2-phenylethyl)l(2H)-virisonyl]viridason; melting point 104.2°C (compound 250): 6-chloro-6-[5-[4-chloro-3-()IJfluoromethyl)phenyl)-3 ,4-Sohydro-1(2H)-pyrisonyl]pyridazine, melting point 140.9°C (compound 25
1); 6-chloro-6-[3-(3-fluorophenyl)-2,3-dihydro-11! -pyrrol-1-yl]viridason; melting point 213.0°G (compound 252); 3-
Chloro-6-[:3-(3-fluorophenyl)-2,
5-dihydro-1H-pyrrol-1-yl]pyridazine;
Melting point 228.8°C (compound 253); 3-C3,6-sohydro4-(6-methylphenyl)-1(2)I)-
Birisonyl]-6-methylpyridazine; melting point 1234℃
(Compound 254): 3-[3,6-sohydro-4-(3
-methylphenyl)-1(2)-pyrisonyl]-6-
Medoxyviridason; melting point 116.4°C (compound 255
): and 6-ptoxy6-C5,6-cyhydro4-(methylphenyl)-1(2H)-zynyl]viridason; melting point 97.8°C (compound 256).

Example 44 5-chloro-6-[4-(3-methylphenyl)-1-piverasonyl]pyridasone 2 was added to a stirred mixture of 80 parts of 1-butanol, 04 parts of sodium hydroxide, and 094 parts of phenol at 60°C. .2 parts were added. The whole was stirred and refluxed over the weekend. The reaction mixture was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was taken from house to house, dried and 6-ptoxy6-(4-
Two parts (3-methylphenyl)-1-biperasonyl]pyridazine (Part 64) were obtained: melting point 105.2°C (compound 2
57).

Example 45 3-chloro-6-[4-(3-methylphenyl)
4 parts of -1-biperasonyl]viritason were added. The whole was stirred and refluxed for 40 hours. After cooling, 25 parts of water were added. The product was filtered off, washed with water and dissolved in trichlormethane. The organic layer was dried, filtered and evaporated.

The residue was crystallized from a mixture of 2-760 panol and 2,2'-oxybispropane. The product was filtered, dried and 3-methoxy-6-[4-(3-methylphenyl)
-1-piperazinyl]viridason 2 parts (50 units) were obtained; melting point 1371°C (compound 258).

Following a similar method and using equivalent amounts of the appropriate starting materials, the following was also prepared: 3-[3,6-sohydro-4-(2,3-dimethylphenyl)-1(2#)-pyrisonyl] -6-Medoxyviridason; melting point 110.8°C (Compound 260); 1-(6-Medoxy-3-viridasonyl)-4-(3-
(methylphenyl)-4-biperisonol; melting point 125.
6°C (compound 261); 3-[3,4-sohydro-4-(6-methylphenyl)
-1(21-virisonyl]-6-ethoxypyridazine;
Melting point 84.3°C (Compound 262): and 1-(6-ptoxy5-byridasonyl)-4-(6-
(methylphenyl)-4-piberisonol; melting point 1067
°C (compound 263).

Example 46 1.9 parts of phenol, 2.9 parts of 6-chloro-6-[4-(3-methylphenyl)-1-biverasonyl]pyridazine
and 276 parts of potassium carbonate was stirred and heated in an oil bath to 150° C. for 7 hours. After cooling, water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-prozenol and 2,2'-oxybispropane. The product is sent door to door, dried and 5-C4-<5-
2 parts of methylphenyl)-1-piperasonyl']-6-fethoxypyridazine (obtained 601; &: melting point 123.4
°C (Compound 264).

In a similar manner, also prepared: 3-(
4-chlorophenoxy)-6-[4-(6-methylphenyli1-biperasonyl]viridason; melting point 1301°C
(Compound 265): and 3-[4-(3-methylphenyl)-1-biperanonyl]-6-(phenylthio)pyridazone; melting point 135.3
°C (Compound 266).

Example 47 To a stirred solution of 0.7 parts of sodium in 20 parts of benzene methanol was added 5.8 parts of 6-chloro-6-[4-(3-methylphenyl)-1-biperasonyl]pyridazone. The whole was stirred and heated to 180°C in an oil bath. - After incubation for the night, water was added and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 2,2'-oxybispropane was added to the residue.

The product was separated into a furnace and mixed with 2-propanol and methanol (7
) was crystallized from the mixture. The product is oven-separated and dried, 3
-[4-(3-methylphenyl)-1-biverasonyl)
-6-(phenylmethoxy)pyridazine 6.4 parts (47
Shima); melting point 159.4°C (Compound 267).

In a similar manner, also prepared: 4-(
6-methylphenyl)l-C6-(phenylmethoxy)
-3-pyridasonyl]-4-biperisonol; melting point 12
4.8°C (Compound 268).

Example 48 4-(3-methylphenyl)-1-[6-(phenylmethoxy)-2-pyridasonyl]-4-piberisonol 6
．． A mixture of 1 part and 250 parts of 2-methoxyethanol was hydrogenated at normal pressure and room temperature using 2 parts of 10 cycles of ξ rasium catalyst supported on charcoal. After absorbing the calculated amount of hydrogen, the catalyst was separated and the F liquid was evaporated. 2-
Boiled in Proper Tools. The product is taken from house to house, dried and 6-[4-hydroxy-4-(3-methylphenyl)
-1-piperidinyl]-3-pyridasonol 4.5 parts (
97); melting point 264.6°C (Compound 269).

6-[4-hydroxy-4-(3-methylphenyl)-
1-biperisonyl]-6-pyridasonol 29 parts, 6N
A mixture of 60 parts of hydrochloric acid solution and 24 parts of ethanol was stirred at reflux temperature for 2 hours. The reaction mixture was evaporated. Crushed ice was added and the whole was treated with concentrated ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified on silica gel using a mixture of trichloromethane and methanol (98%) as eluent.
:2 volume ratio) was used for purification by column chromatography. The pure fractions were collected and the eluent was evaporated. The residue was diluted with 2-pZ/- and 2.2'-
Crystallized from an oxybispropano mixture. The product is taken from house to house, dried and converted into 6-(3,6-sohydro-4-(6-
methylphenyl)-1(2-horn)-bilisonyl)-3-
Two parts (75%) of HiIJ Dasonol were obtained; melting point 179.
0'C (compound 270).

Example 49 A mixture of 6 parts of 3-(4-(3-methylphenyl)-1-piperazinyl:]-6-(phenylmethoxy) viridazone and 60 parts of concentrated hydrochloric acid was stirred for 3 hours and refluxed. The product was left to stand overnight and treated with concentrated ammonium hydroxide. The product was taken apart, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was dissolved in 2-OA/ -2.2'-oxybispropano mixture. The product was separated, dried and
-(4-(3-methylphenyl)-1-piperazinyl)
45 parts of -3(2R)-viridasonone (98 winters) were obtained;
Melting point: 2098°C (Compound 271).

Example 50 5-chloro-6-C4-(4-methoxyphenyl)-1
-Viberasonil] Viridasone Z (3 parts) was hydrogenated using an acid at normal pressure and room temperature. After absorbing the calculated amount of hydrogen,
The catalyst was furnace separated on the top of the pipe, and the furnace liquid was evaporated. 2 residues
- crystallized from propatool, 3-[4-(4-methoxyphenyl)=1-piperazinyl]viridason 4.11
(63, 2); melting point 133.4°C (compound 27
2).

Example 51 3-chloro-/)-[4-(3-methylphenyl)-1
-Piperazinyl] A mixture of 58 parts of viridazone and 3 parts of thiourea was stirred in an oil bath at 165°C for 3 hours. After cooling, 150 parts of 05N sodium hydroxide solution were added. The whole was stirred and refluxed for 15 minutes. This product was filtered while hot, and the P solution was neutralized with acetic acid. The product was separated, washed with water and separated by column chromatography on silica gel using a mixture of trichloromethane and methanol (985:1.5 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and tetrahydrofuran. The product was separated and dried to obtain 1.3 parts (22.7 parts) of 6-[4-(3-methylphenyl)-1-biperasonyl]-6-viridasonthiol; melting point 1742.
°C (Compound 276).

Example 52 To a stirred solution of 0.92 parts of sodium in 8 parts of methanol was added 45 parts of benzene. Distilling off methanol,
Next, 6.2 parts of methyl 6-[4-(3-methylphenyl)-1-biperasonyl]-3-pyridazinecarboxylate in 45 parts of benzene and 35 parts of ethyl acetate were added. The whole was stirred and refluxed overnight. The reaction mixture was evaporated.

100 parts of water was added. The mixture was acidified with 24 parts of concentrated hydrochloric acid, boiled for 2 hours, cooled and treated with sodium bicarbonate. The product was filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-gropanol and 2,2'-oxybisglopanol/4'. The products are distributed door to door.
Dry, 1-[:6-[4-(3-methylphenyl)-
1-piperasonyl]-6-pyridasonyl]etha, non-6
(51 parts); melting point 135.9°C (compound 274
).

In a similar manner, the following were also prepared: =1-[
6-[3,6-sihydro-4-(6-methylphenyl)
-1(2'#)-pyridinyl]-6-pyridazinyl]ethano/; melting point 115.0°C (compound 275).

Example 53 To illustrate the useful antiviral properties of the compounds of the present invention, a number of such compounds were tested in the rhinovirus cytopathology efficacy studies described above.

These compounds are summarized in the table below along with the test results.

D0 composition example "Active Ingredient" (A) as used in the Examples below.

1,) relates to compounds of formula (I), their possible stereochemically isomeric forms or their pharmaceutically acceptable acid addition salts.

Example 54: Oral dololag, 4.7.5004, with 0.2-hydroxypropionic acid.
5 and polyethylene glycol 1.5tK6cJ~8
Dissolved at 0°C. After cooling to 60-40°C, 55 t of polyethylene glycol was added, and the mixture was thoroughly stirred. Next, add 2.5 ml of purified water to 175 ml of sodium saccharin.
Add the solution of 01 and add the cocoa flavoring agent 2.5 while stirring.
and a sufficient amount of polyethylene glycol to give a volume of 50 tons to produce an oral drop solution consisting of 1.10 #v of A per ml. The resulting solution was filled into suitable containers.

Example 55: Oral Solution 9 v of methyl 4-hydroxybenzoate and 1 part of propyl 4-hydroxybenzoate were dissolved in 4 t of boiling purified water. Into this solution 6, first 2,3-dihydroxybutanedioic acid'+Of and then A, 1.20r were dissolved. Combine the latter solution with the remainder of the former solution and add 1
．． 2. 12 3-Pro, J-triol and 3 t of 70% sorbitol solution were added. sodium saccharin 40
2 in water, dissolve in 5t, and add Ezoichigo Essence 2Wn
t and 2 ml of Jasperum guriessense were added. The latter solution was combined with the former solution and enough water was added to give a volume of 20 tons to produce an oral solution consisting of 20a7 of active ingredient per teaspoon (5ml).

The resulting solution was filled into a suitable container.

Example 56: Capsule A, 1.20f, sodium lauryl sulfate 6f.

56 vol of starch, 562 ml of lactose, 0.8 f of colloidal silicon dioxide and 1.21 f of magnesium stearate were stirred together vigorously. The resulting mixture was then filled into 1000 suitable hard gelatin capsules, each capsule containing 20 m9 of active ingredient.

Example 57: Production of film laminated tablet tablet core A, 1.100f, lactose 570f and starch 200
Thoroughly mix the mixture of 7, 52% of sodium dodecyl sulfate and 102% of polyvinylpyrrolidone in 200 pieces of Honsuri.
moistened with a solution of Pass the wet powder mixture through a sieve;
Dry and pass through a sieve again. Next, microcrystalline cellulose 1002 and hydrogenated plant 15S' were added. The whole was thoroughly mixed and compressed into tablets to produce 10,000 tablets each containing 10 to 10 active ingredients.

Coated denatured ethanol 75m? A solution of 52 ml of ethylcellulose in 150 mA of dichloromethane was added to a solution of 10 ml of methylcellulose in the solution. Then 75 ml of sochloromethane and 25 ml of 1,2,3-propanetriol were added. Melt 1 (l) of polyethylene glycol and dissolve in 75 ml of sochloromethane (1 VC). The latter solution was added to the former solution, then 2.5 F of magnesium octadecanoate, 75 F of polyvinyl pyrrolid and a concentrated dye suspension (0 paspray
K-1-21091 was added and the whole was homogenized.

Tablet cores were coated with the mixture thus obtained in a coating apparatus.

Example 58 Two injection solutions: 1.8 ml of methyl 4-hydroxybenzoate and 0.2 y of propyl 4-hydroxybenzoate in boiling water for injection.
It was dissolved in 1. After cooling to about 50°C, while stirring,
Lactic acid 47, propylene dalicol 0, D5r and A, 1
．． Added 4f. The solution was cooled to room temperature and the volume was 1 tV.
Sufficient water for injection was added to prepare a solution containing A, I, and 4 arg per ffIe. Sterilize this solution by filtration.U, S, P.

XVIIp, a111, filled into a sterile container.

Example 59: Suppository A, 1. y and t are polyethylene glycol 400.25
Dissolved in a solution of 2,5-dihydroxybutanedioic acid 61 in rn/. Sufficient triglycerides were melted together to make surfactants 12f and 600f. The latter mixture was thoroughly mixed with the former solution. The mixture thus obtained was poured into molds at a temperature of 67-68°C to form 100 suppositories, each containing 60 g of active ingredient.

Continuing from page 1 ■Int, C1, 4 Identification code Office serial number ■Int, C
1,4 Identification symbol Internal serial number ■Int, C1, 'Identification symbol Internal serial number Priority claim [Phase] 198 Next Makizuki 15th [
United States of America (US) 702772 @ Inventor: Marcel Joseph
9 Inventor Joannes Josephus Belgium B Maria Willems - Sprongdre 0 Inventor Marcel Gereberne Belgium Piece Maria Luix 31 2460 - Force Stelleley φ Force Stuttenberg 2360 - Autotournhout Towef 4

Claims (1)

[Claims] 1. In the formula, R1 is hydrogen, halo, IH-imidazol-1-yl, lower alkyloxy, aryloxy, aryl lower alkyloxy, lower alkylthio, arylthio, hydroxy, mercapto, amino, lower alkyl is a member selected from the group consisting of sulfinyl, lower alkylsulfonyl, cyano, lower alkyloxycarbonyl, lower alkyl carbonyl and lower alkyl; R2 and Bs are each independently selected from the group consisting of hydrogen and lower alkyl; , Mataha R2 and Hin3 Hate
a can form a divalent group of the formula -cH=cs-C) (=CH-; A is the formula %formula%()) and one of the hydrogen atoms in may be substituted with: m and n are each independently an integer from 1 to 4,
and the sum of m and n is 3.4 or 5; R4 is hydrogen; lower alkyl; aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl; lower alkyloxycarbonyl; aryl lower alkyl;
Diaryl lower alkyl; phenyl substituted with arylcarbonyl; pyridinyl optionally substituted with cyano or lower alkyl; optionally substituted with up to two substituents independently selected from the group consisting of cyano and aryl; a member selected from the group consisting of both cyclohexyl and cyclohexenyl; Bs is hydrogen; lower alkyl; aryl: hydroxy; lower alkyloxy; aryloxy; lower alkyloxy substituted with morpholine, pyrrolidine or piperidine; amino ; (lower alkyloxycarbonyl) amino; arylamino; (aryl) (lower alkyl) amino; (aryl lower alkyl) amino; (aryl lower alkenyl) amine; (aryl lower alkenyl) (lower alkyl) amino; Yes; R6 is hydrogen; aryl; lower alkyl; (lower alkylcarbonylamino) lower alkyl; aryl lower alkyl; arylcarbonyl lower alkyl; aminocarbonyl; arylcarbonyl; arylaminocarbonyl;
(aryl lower alkyl) carbonyl; lower alkyloxycarbonyl; indolyl; pyridinyl; Rt and R8 are each independently hydrogen, lower alkyl,
Aryl is a member selected from the group consisting of aryl, aryl lower alkyl and pyridinyl; said aryl is a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, nitro, amine, lower alkyloxy, hydroxy and lower alkyloxycarbonyl; chenyl; and naphthalenyl. Compounds of phenyl, optionally substituted with up to three substituents each independently selected from the group, their pharmaceutically acceptable acid addition salts and/or their possible stereochemically isomeric forms and A method for treating a viral disease in a warm-blooded animal suffering from a viral disease, comprising systemically administering to the warm-blooded animal an antivirally effective amount of a possible tautomeric form thereof. 2. The method according to claim 81, wherein the viral disease is caused by rhinovirus. a, l(, I, R2 and R3 are hydrogen and A is a group of formula (b), 1(4 is other than 3,3-diphenylglopyl; R1 is hydrogen) , and R2 and R8 combine to form a divalent CH=CH-CH=CH
is other than -IH-azepinyl; when R1 is halo, Rt is lower alkyl and R1 is hydrogen; R1 is chloro and A is ), R14 is other than (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α-methyl-phenethyl or (2-methylphenyl)methyl, the method according to claim 1 . 4. R", R" and R1 are hydrogen and A has the formula Φ
), R4 is other than 3,3-diphenylpropyl: R1 is hydrogen and R2 and R3 combine to form a divalent CH=CH-CH=CH group; if R1 is halo, R2 is lower alkyl and R'' is hydrogen, other than -IH-azepinyl: 1(, I is chloro and A is of the formula (b ), R4 is other than (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α-methyl-phenethyl or (2-methylphenyl)methyl, Claim I
The method described in Section A2. 5, A is a group of the formula (a>, (C), (d) or 1(4-C-cmN(2m-N-〇nH2n-(b-1); provided that m and n are the above-mentioned and the group CmH2m, C
One of the hydrogen atoms in rr, , H2(m-1) or CnH2n may be substituted with lower alkyl or aryl; and R is aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl, lower alkyloxy carbonyl; aryl lower alkyl; diaryl lower alkyl; phenyl substituted with aryl carbonyl; pyridinyl optionally substituted with cyano or lower alkyl; with up to two substituents independently selected from the group consisting of cyano and aryl; A member selected from the group consisting of both optionally substituted cyclohexyl and cyclohexenyl; with the conditions: 1) When A is a group of formula (C) and R6 is hydrogen, Rs is other than hydrogen, hydroxy or lower alkyl; 1i) when R', R'' and R3 are hydrogen and A is a group of formula (b-1), R4-0 is 3,3-diphenyl; other than propyl; 1ii) R'' and R3 are hydrogen and A is of formula (a
), R1 is other than halo; 1v) When R' is chloro, R2 and R3 are hydrogen, and A is a group of formula (b-1), R is other than 2-methoxyphenyl; v) When R' is chloro and A is a group of formula (b-1), R4-C is (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, 2. The method according to claim 1, which is other than α-methyl-phenethyl or (2-methylphenyl)methyl. 6, A is a group of formula (a), (C), (d) or 4-C-CmH2m-N-CnH2n-(b-1): provided that m and n have the above meanings, and the group CmH2msC
One of the hydrogen atoms in m-IH2(m-1) or CnH2n may be substituted with lower alkyl or aryl; and R4-0 is aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl, lower alkyloxy selected from the group consisting of carbonyl; aryl lower alkyl; diaryl lower alkyl; phenyl substituted with arylcarbonyl; both cyclohexyl and cyclohexenyl, optionally substituted with up to one substituent, cyano or lower alkyl; 1) When A is a group of formula (C) and R is hydrogen, R' is other than hydrogen, hydroxy or lower alkyl; 1i) R'', R ``and RA are hydrogen, and A is a group of formula (b-1), R4-0 is other than 3,3-diphenylgropyl; +ii) R'' and R are hydrogen; , and A is the formula (a
), R1 is other than halo; +V) When R1 is chloro, R2 and R3 are hydrogen, and A is a group of formula (b-1'), R is 2-
other than methoxyphenyl: v) When R' is chloro and A is a group of formula (b-1), R4-0 is (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α- 3. The method of claim 2, which is other than methyl-phenethyl or (2-methylphenyl)methyl. 7. A is a group of formula (b), provided that R4 is aryl, pyridinyl, pyrimidinyl, lower alkyloxycarbonyl, aryl lower alkyl, diaryl lower alkyl, quinolinyl 21 [Ill group, or A is a group of formula (C) , where R1 is hydrogen, aryl, arylamino, (aryl)(lower alkyl)amino, hydroxy, indolyl, and R6 is hydrogen, aryl, arylcarbonyl, (arylcarbonyl)lower alkyl. or A is a divalent group of formula (d). 8A is formula (b), provided that R4 is aryl, pyridinyl,
is a divalent group which is pyrimidinyl, lower alkyloxycarbonyl, aryl lower alkyl, diaryl lower alkyl, quinolinyl, or A is of formula (C), provided that R5 is hydrogen, aryl, arylamino, (aryl) (lower alkyl) amino, hydroxy, indolyl, and R6 is hydrogen, aryl, arylcarbonyl, (arylcarbonyl)lower alkyl, or A is a divalent group of formula (d) A method according to claim 6. 9. The method according to claim 7, wherein both R2 and Ba are hydrogen. 10. The method according to claim 8, wherein lO, R'' and R3 are both hydrogen. 11. In the divalent group A having formula (b), m is an integer 2 or 3, and n is 2 and having the formula (C), m is an integer 1 or 2, and n is an integer 2, and in the group A of formula (d), m
The method according to claim 9, wherein n is an integer l or 2, and n is an integer 2. 12, in the divalent group A having the formula (b), m is an integer 2 or 3, and n is 2; in the group A having the formula (C), m is an integer l or 2; and n is an integer 2, and in the group A of formula (d), m
11. The method of claim 10, wherein is an integer 1 or 2, and n is an integer 2. 13. The method according to claim 11, wherein R' is halo, lower alkyloxy, aryloxy, lower alkylthio, arylthio and cyano. 14. The method according to claim 12, wherein R' is halo, lower alkyloxy, aryloxy, lower alkylthio, arylthio and cyano. 15. The method of claim 11, wherein R' is halo. 16. The method of claim 12, wherein R1 is halo. 17. The method according to claim 1, wherein the compound is 3-bromo-6-(4-(3-methylphenyl)-1-piperazinyl)pyridazine. 18. The method according to claim 1, wherein the compound is 3-bromo-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. -(3-methylphenyl)-1-piperazinyl] hyritacin, the method according to claim 2. 19. The compound is 3-chloro-6-[3,6-cyhydro-4-(3-methylphenyl) -1(2H)-pyridinyl]pyridazine. 20. The compound is 3-chloro-6-[3,6-cyhydro-4-(3-methylphenyl)-1(2H )-pyridinyl]pyridazine. 21. As an inert carrier and an active ingredient, R1 is hydrogen, halo, IH-imidazol-1-yl, lower alkyloxy, aryloxy, R2 and R3 are members selected from the group consisting of aryl lower alkyloxy, lower alkylthio, arylthio, hydroxy, mercapto, amino, lower alkylsulfinyl, lower alkylsulfonyl, cyano, lower alkyloxycarbonyl, lower alkyl carbonyl and lower alkyl; are each independently selected from the group consisting of hydrogen and lower alkyl, or R' and R can be interlocked to form a divalent group of the formula -CH=CH-CH=C) (- ;A is the formula %() (1)) One of the atoms may be substituted with lower alkyl or aryl; m and n are each independently an integer from 1 to 4;
and the sum of m and n is 3.4 or 5; R4 is hydrogen; lower alkyl; aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl;
lower alkyloxycarbonyl; aryl lower alkyl; diaryl lower alkyl; phenyl substituted with arylcarbonyl; pyridinyl optionally substituted with cyano or lower alkyl; up to 2 elements X independently selected from the group consisting of cyano and aryl is a member selected from the group consisting of both cyclohexyl and cyclohexenyl, which may be optionally substituted with a substituent; Bs is hydrogen; lower alkyl; aryl; hydroxy; lower alkyloxy; aryloxy; morpholine, pyrrolidine or lower alkyloxy substituted with piperidine: amino; (lower alkyloxycarbonyl) amino: arylamino; (aryl) (lower alkyl) amino: (aryl lower alkyl) amino; (aryl lower alkenyl) amino; (aryl lower alkenyl )(lower alkyl)amino; arylcarbonyloxy: R@ is hydrogen; aryl: lower alkyl; (lower alkylcarbonylamino) lower alkyl; aryl lower alkyl: arylcarbonyl lower alkyl; aminocarbonyl; arylcarbonyl; arylaminocarbonyl ;
(aryl lower alkyl) carbonyl; lower alkyloxycarbonyl; indolyl; pyridinyl; By and R6 are each independently hydrogen, lower alkyl,
Aryl is a member selected from the group consisting of aryl, aryl lower alkyl and pyridinyl; said aryl is a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, nitro, amine, lower alkyloxy, hydroxy and lower alkyloxycarbonyl; chenyl; and naphthalenyl. is phenyl optionally substituted with up to three substituents each independently selected from the group, its pharmaceutically acceptable acid addition salts and/or its possible stereochemically isomeric forms and and/or an antiviral composition containing an antivirally effective amount of a possible tautomeric form thereof. 22, , R1, f4. and R1 is hydrogen and A is a group of formula (b), R4 is other than 3,3-diphenylpropyl; R1 is hydrogen and R2 and R3 are bonded; divalent CH=CHcH=CH
if R1 is halo and R2 is lower alkyl other than piperidinyl and hexahydro-IH-azepinyl; if R1 is chloro and A is a group of formula Φ) , R4 is (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α-methyl-phenethyl or (2
22. The antiviral composition of claim 21, which is other than -methylphenyl)methyl. 23, A is a group of formula (a), (C), (d) or 4-C-CmH2m-N-CnH2n-(b-1); provided that m and n have the above meanings, And the group CmH2m゛・
One of the hydrogen atoms in Cm-1Cm-1H2 (or CnH2n may be substituted with lower alkyl or aryl; and R4-0 is aryl; thiazolyl; pyrimidinyl; quinolinyl; lower alkylcarbonyl, lower alkyloxycarbonyl; A member selected from the group consisting of: aryl lower alkyl; diaryl lower alkyl; phenyl substituted with arylcarbonyl; both cyclohexyl and cyclohexenyl, optionally substituted with cyano or lower alkyl, with up to one substituent. with the proviso that 1) when A is a group of formula (C) and R6 is hydrogen, R1 is other than hydrogen, hydroxy or lower alkyl; ``is hydrogen and A is a group of formula (b-1), R4-C is other than 3,3-diphenylpropyl; 1ii) R'' and R3 are hydrogen and A is the formula (a
), R1 is other than halo; 1v) When R' is chloro, R1 and R3 are hydrogen, and A is a group of formula (b-1), R is other than 2-methoxyphenyl; V) When R' is chloro and A is a group of formula (b-1), R4-0 is (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, The antiviral composition according to claim 21, which is other than α-methyl-phenethyl or (2-methylphenyl)methyl. 24, A is the formula Φ), provided that R4 is a divalent group which is aryl, pyridinyl, pyrimidinyl, lower alkyloxycarbonyl, aryl lower alkyl, diaryl lower alkyl, quinolinyl, or A is the formula (C), provided that ,B,
s is hydrogen, aryl, arylamino, (aryl) (
lower alkyl)amine, hydroxy, indolyl, and R6 is hydrogen, aryl, arylcarbonyl,
The antiviral composition according to claim 21, wherein (arylcarbonyl) is a divalent group of lower alkyl, or is a divalent group of formula (d). 25. The antiviral composition according to claim 24, wherein both R'' and R3 are hydrogen. 26. In the divalent group A having the formula ), m is an integer 2
or 3, and n is 2, in the group A having formula (C), m is the integer l or 2, and n
is an integer 2, m is an integer 1 or 2, and n is an integer 2 in the group A of the button formula (d), The antiviral composition according to claim 25. 27. The antiviral composition according to claim 26, wherein R1 is halo, lower alkyloxy, aryloxy, lower alkylthio, arylthio, and cyan. 28. The antiviral composition according to claim 26, wherein R' is halo. 29. The antiviral composition according to claim 21, wherein the compound is 3-bromo-6-C4-(3-methylphenyl)-1-piperazinyl]pyridazine. 30. 22. The antiviral composition according to claim 21, wherein the compound is 3-chloro-6-[3,6-cyhydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine. 31, Formula % Formula % In the formula, R1 is hydrogen, halo 1. IH-imidazol-1-yl, lower alkyloxy, aryloxy, aryl lower alkyloxy, lower alkylthio, arylthio,
a member selected from the group consisting of hydroxy, mercapto, amino, lower alkylsulfinyl, lower alkylsulfonyl, cyano, lower alkyloxycarbonyl, lower alkyl carbonyl and lower alkyl; selected from the group consisting of alkyl or R2 and R1 can be combined to form a divalent group of the formula -CH=CH-CH=CH-; A! One of the hydrogen atoms in the formula %() ) () may be substituted with lower alkyl or aryl; m and n are each independently an integer from 1 to 4,
and the sum of m and n is 3.4 or 5; R4-0 is substituted with aryl: thiazolyl; pyrimidinyl; quinolinyl; lower alkyl carbonyl, lower alkyloxycarbonyl; aryl lower alkyl; diaryl lower alkyl; aryl carbonyl Phenyl; pyridinyl optionally substituted with cyano or lower alkyl; consisting of both cyclohexyl and cyclohexenyl optionally substituted with up to two substituents independently selected from the group consisting of cyano and aryl a member selected from the group: with the proviso that 1) when A2 is a group of formula (C) and R6 is hydrogen, Rs is other than hydrogen, hydroxy or lower alkyl; 11) R1, When R' and Rs are hydrogen and A is a group of formula (b-1), R4-0
is other than 3,3-diphenylglopyr; +1i) R'' and R3 are hydrogen and A2 is of the formula (
a), R1 is other than halo; 1v) R' is chloro, R' and R3 are hydrogen, and A! is a group of formula (b-1), R4-C is other than 2-methoxyphenyl; v) when R' is chloro and A2 is a group of formula (b-1>), R4-0 is other than (dimethoxyphenyl)methyl, (dimethoxyphenyl)ethyl, α-methyl-phenethyl or (2-methylphenyl)methyl; a pharmaceutically acceptable acid addition salt thereof; and/or its possible stereochemical isomeric forms and/or its possible tautomeric forms. 32, A" is 2Φ), provided that R4-0 is aryl, pyridinyl, pyrimidinyl, lower alkyloxycarbonyl, aryl lower alkyl, diaryl, lower alkinobequinolinyl, or AR is a divalent group of formula (C),
However, R5 is hydrogen, aryl, arylamino, (aryl)(lower alkyl)amine, hydroxy, indolyl, and R6 is hydrogen, aryl, arylcarbonyl, (arylcarbonyl)lower alkyl.
32. The compound according to claim 31, wherein At is a divalent group of formula (d). 33. The compound according to claim 32, wherein both R'' and 几3 are hydrogen. 34. In the divalent group A! having Φ), m is an integer 2 or 3, and n is an integer 2, and the formula (C)
A group having A! , m is an integer 1 or 2,
and n is an integer 2, and in group A2 of formula (d), m is an integer 1 or 2, and n is an integer 2. 35. The compound according to claim 34, wherein R'' is halo, lower alkyloxy, aryloxy, lower alkylthio, arylthio, and cyano. 36. The compound according to claim 34, wherein R' is halo. Compound. 37,3-bromo-6-[4-(3-methylphenyl)
-1-piperazinyl] A compound selected from the group consisting of pyridazine and a pharmaceutically acceptable acid addition salt thereof. 38,3-chloro-6-(3,6-sihydro-4-(3
-methylphenyl)-1(2H)-pyridididinyl pyri? and pharmaceutically acceptable acid addition salts thereof. 39, where R1 is hydrogen, halo, IH-imidazol-1-yl, lower alkyloxy, aryloxy, aryl lower alkyloxy, lower alkylthio, arylthio, hydroxy, mercapto, amino, lower alkylsulfinyl, lower alkylsulfonyl, is a member selected from the group consisting of cyano, lower alkyloxycarbonyl, lower alkylcarbonyl and lower alkyl; R2 and Bs are each independently selected from the group consisting of hydrogen and lower alkyl, or R1 and Bs are can be combined to form a divalent group of the formula -CH=CH-CH=CH-; A2 is a divalent group of the formula %()); the group CmH2msCm-In2(m-1 ) or CnH2
One of the hydrogen atoms in n may be substituted with lower alkyl or aryl and may be 0; m and n are each independently an integer from 1 to 4,
and the sum of m and n is 3.4 or 5; R4-0 is substituted with aryl; thiazolyl: pyrimidinyl; quinolinyl: lower alkyl carbonyl, lower alkyloxycarbonyl; aryl lower alkyl; diaryl lower alkyl; aryl carbonyl Phenyl; pyridinyl optionally substituted with cyano or lower alkyl; consisting of both cyclohexyl and cyclohexenyl optionally substituted with up to two substituents independently selected from the group consisting of cyano and aryl As a selected member of the group and as a double character: 1) when A2 is a group of formula (C) and R6 is hydrogen, 几ゝ is other than hydrogen, hydroxy or lower alkyl; 1+) R ', R'' and R''ffi are hydrogen, and when A is a group of formula (b-1), R
4-0 is other than 3,3-diphenylglopyr; 1ii) R'' and R3 are hydrogen and At is of the formula (
a), R1 is other than halo; IV) R' is chloro, R2 and R3 are hydrogen, and A2 is a group of formula (b-1), then B4- C is other than 2-methoxyphenyl; V) When R' is chloro and At is a group of formula (b-1), R4-0 is (dimethoxyphenyl)methyl, (dimethoxyphenyl) ) other than ethyl, α-methyl-phenethyl or (2-methylphenyl)methyl, a pharmaceutically acceptable acid addition salt thereof and/or
or its possible stereochemically isomeric forms and/or its possible tautomeric forms, the amine of formula a) is optionally prepared in a reaction-inert solvent, optionally in the presence of a base. alkylated with a pyridazine of the formula in which W represents a reactive leaving group; b) a pyridazine amine of the formula % is optionally reacted with a pyridazine amine of the formula % in a solvent inert to the reaction, optionally in the presence of a base; % formula % () where B4-a is R4 provided that it is not hydrogen and W represents a reactive leaving group, thus forming a compound of formula C) Pyridazine amine of formula (1-71) is reacted with formula 4-b-1 (R)=c= in a solvent inert to the reaction. -4-b-1. In the formula, (R)=c=o is a group of formula R4rbH, -
The CH,- group is oxidized to a carbonyl group and B4-b
is reductively N-alkylated with a carbonyl compound of aryl lower alkyl, diaryl lower alkyl, cyclohexyl or cyclohexenyl, thus producing a compound of formula; The compound is converted to the therapeutically active non-toxic acid addition salt by treatment with a suitable acid, or conversely, the acid addition salt is converted to the free base form by an alkali: and/or its stereochemical isomerism The formula (I") characterized in that it produces a body shape
), its pharmaceutically acceptable acid addition salts and/or its possible stereochemically isomeric forms and/or its possible tautomeric forms.